TW201331193A - Fused imidazole derivatives as TRPV3 antagonsit - Google Patents

Abstract

The present invention provides transient receptor potential vanilloid (TRPV) modulators of formula (I). In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPV3. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPV3.

Description

A fused imidazole derivative as a TRPV3 antagonist

The present invention generally relates to fused imidazole derivatives having transient receptor potential vanilloid 3 (TRPV3) antagonist activity.

Ion movement is achieved through the cell membrane through specialized proteins. The TRP channel is a large family of non-selective cation channels that help regulate ion current and membrane potential. The TRP channel is divided into six subfamilies including the TRPV family. TRPV3 is a member of the TRPV class of the TRP channel.

TRPV3 is a calcium-permeable channel, especially a calcium-permeable, non-selective cation channel. In addition to calcium ions, the TRPV3 channel is permeable to other cations such as sodium ions. Thus, the TRPV3 channel regulates membrane potential by modulating the flow of cations such as calcium and sodium ions. The TRPV3 receptor differs in mechanism from the voltage-gated calcium channel. Typically, voltage-gated calcium channels respond to membrane depolarization and open channels to allow calcium ions to flow from the extracellular matrix, causing an increase in intracellular calcium levels or concentrations. In contrast, non-selective long-lasting TRP channels are usually ligand-gated (via chemical reagents such as 2-aminoethoxydiphenyl borate [2-APB], vanilloid (vanilloid) ) and heat are adjusted) and produce longer lasting changes in ion concentration. These differences in mechanism are accompanied by differences in the structure of the voltage-gated channel and the TRP channel. Thus, although there are many different channels in various cell types and in response to numerous stimuli that act to regulate ion flux and membrane potential, it is recognized that the significant differences in structure, function, and mechanism between different types of ion channels are significant. important.

TRPV3 protein is in skin cells (Peier et al, Science (2002), 296, 2046-2049) and dorsal root ganglia, trigeminal ganglia, spinal cord and brain (Xu et al, Nature (2002), 418, 181-185; Smith Etc., Thermosensitive channels expressed in Nature (2002), 418, 186-188). TRPV3 is also highly expressed in the skin. In keratinocyte cell lines, stimulation of TRPV3 causes release of an inflammatory mediator such as interleukin-1. Therefore, TRPV3 also plays an important role in regulating pain and inflammation caused by the release of inflammatory stimuli. As described herein, in particular, the TRPV3 protein can be used in screening assays to identify compounds that modulate the function of TRPV3, including but not limited to human TRPV3, mouse TRPV3, rat TRPV3, and Drosophila TRPV3. The sequence corresponding to human TRPV3, mouse TRPV3 and Drosophila TRPV3 is disclosed in US 2004/0009537 (the '537 application). For example, SEQ ID Nos 106 and 107 of the '537 application correspond to human nucleic acid sequences and amino acid sequences, respectively. SEQ ID Nos 108 and 109 of the '537 application correspond to the nucleic acid sequence and the amino acid sequence of the mouse, respectively.

The function of TRPV3 basically involves the reception and transduction of pain. Therefore, it is desirable to identify and produce compounds that modulate one or more functions of TRPV3.

WO 2007/056124, WO 2006/017995, WO 2008/140750 and WO 2008/033564 disclose TRPV3 modulators, in particular antagonists, for the treatment of a variety of TRPV3-mediated diseases. Benzopyran derivatives are disclosed in WO 2006/065686 and WO 2007/042906; WO 2009/084034, WO 2009/109987 and WO 2009/130560 disclose different stents for TRPV3 modulators, especially for TRPV3 antagonists (scaffolds).

In the effort to discover better analgesics, there is still a need for therapeutic treatment of diseases, conditions and/or disorders regulated by TRPV3.

In one aspect, the invention provides a compound of formula (I) having TRPV3 antagonist activity:

Or a pharmaceutically acceptable salt thereof, wherein X is independently selected from C or N; when X is N, it is optionally oxidized to form an oxide of N; and R ^{1 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro , cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, -S(O) _p R ⁵ (wherein p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm' is an integer from 1 to 4, inclusive; Q is hydrogen, substituted or not Substituted alkyl, haloalkyl, aryl, arylalkyl, heteroaryl; wherein the substituent may be one or more, and independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl and cycloalkoxy; R ² and R ³ may be the same or different, independently Selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl , heteroaryl, heteroarylalkyl, hetero Alkyl group and a heterocyclic group; R ⁴ is independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, -COOR ^a, a substituted or unsubstituted alkyl group, alkenyl group, alkoxy group, haloalkoxy , haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl; R ^{a is} independently hydrogen or substituted or unsubstituted alkyl; R ⁵ And R ⁶ may be the same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, cycloalkylalkyl, arylalkyl and heteroaryl Alkyl; and 'n' is an integer from 1 to 3, inclusive.

According to one embodiment, provided is a compound of formula (II):

Or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -S(O) _p R ⁵ (where p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm ' is an integer from 1 to 4, inclusive; Q is hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, arylalkyl, heteroaryl; wherein the substituent may be One or more, and independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, Haloalkoxy, cycloalkyl and cycloalkoxy; R ^a is hydrogen or substituted or unsubstituted alkyl; R ² and R ³ may be the same or different and are independently selected from the group consisting of hydrogen: , substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero a cyclic group and a heterocyclic alkyl group; And R ⁵ and R ⁶ may be the same or different, are independently selected from hydrogen, a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, cycloalkylalkyl, arylalkyl and Heteroarylalkyl.

According to one embodiment, as specifically provided is a compound of formula (II) wherein R ¹ is halogen (e.g. F, Cl or Br), alkyl (e.g. methyl), alkoxy (e.g. methoxy), haloalkoxy a group (e.g., a trifluoromethyl group) or a haloalkoxy group (e.g., difluoromethoxy, trifluoromethoxy); and 'm' is 1, 2 or 3.

According to another embodiment, specifically provided is a compound of formula (II) wherein Q is a substituted or unsubstituted aryl group, preferably a phenyl group.

According to another embodiment, specifically provided are compounds of formula (II) wherein Q is a substituted or unsubstituted arylalkyl group, preferably a benzyl group.

According to another embodiment, specifically provided are compounds of formula (II), wherein Q is substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), heteroaryl, preferably Is a pyridine, pyridazine, pyrimidine, thiophene, thiazole, benzothiazole. In this embodiment, the substituent on the aryl, arylalkyl or heteroaryl group may be one or more and independently selected from the group consisting of halogen, nitro, cyano, amine, -COOH, COOCH ₃ , COOC ₂ H ₅ , C(O)NH ₂ , alkyl, alkoxy, haloalkyl and haloalkoxy.

According to another embodiment, specifically provided are compounds of formula (II) wherein R ² is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl.

According to another embodiment, specifically provided are compounds of the formula (II) wherein R ³ is hydrogen, alkyl (e.g. methyl) or haloalkyl (e.g. difluoromethyl).

According to another embodiment, provided is a compound of formula (III):

Or a pharmaceutically acceptable salt thereof, wherein X is C or N; when X is N, it is optionally oxidized to form an oxide of N; Z is independently selected from C or N; and R ^{1 is} independently selected from hydrogen, Halogen, hydroxy, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, hetero Aryl, heteroarylalkyl, -S(O) _p R ⁵ (wherein p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm' is an integer from 1 to 4, inclusive; ⁷ may be the same or different and are independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, Haloalkoxy, cycloalkyl and cycloalkoxy; R ^a is hydrogen or substituted or unsubstituted alkyl; R ² and R ³ may be the same or different and are independently selected from the group consisting of hydrogen: , substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroaryl Alkyl and heterocyclylalkyl; R ⁵ and R ⁶ may be the same Or different, independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; r' is an integer from 1 to 5, inclusive.

According to one embodiment, as specifically provided is a compound of formula (III) wherein R ¹ is halogen (e.g. F, Cl or Br), and 'm' is 1, 2.

According to another embodiment, specifically provided are compounds of formula (III), wherein Q is a substituted or unsubstituted aryl group, preferably a phenyl group.

According to another embodiment, specifically provided are compounds of formula (III) wherein Q is substituted or unsubstituted arylalkyl, preferably benzyl.

According to another embodiment, specifically provided are compounds of formula (III), wherein Q is substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), heteroaryl, preferably Is a pyridine, pyridazine, pyrimidine, thiophene, thiazole, benzothiazole. In this embodiment, the substituent on the aryl, arylalkyl or heteroaryl group may be one or more and independently selected from the group consisting of halogen, nitro, cyano, amine, -COOH, COOCH ₃ , COOC ₂ H ₅ , C(O)NH ₂ , alkyl, alkoxy, haloalkyl and haloalkoxy.

According to another embodiment, specifically provided are compounds of formula (III) wherein R ² is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl.

According to another embodiment, specifically provided are compounds of the formula (III) wherein R ³ is hydrogen, alkyl (e.g. methyl) or haloalkyl (e.g. difluoromethyl).

It will be understood that the formulae (I), (II) and (III) structurally encompass all geometric isomers, stereoisomers, enantiomers and all that can be considered by the chemical structures of the species described herein. Diastereomers as well as pharmaceutically acceptable salts.

According to another embodiment, specifically provided are compounds of formula (I), (II) and (III) or salts thereof, which are less than 10,000 nM, or even less than 1000 nM, 500 nM, 250 nM or 100 nM The IC ₅₀ value inhibits TRPV3 function. In other embodiments, as specifically provided are compounds of formula (the I), Compound (II) and (III) or a salt thereof, or a salt of these compounds IC ₅₀ values of less than 100nM in inhibiting TRPV3 function, the IC ₅₀ value than the The best is determined by the methods described herein.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the pharmaceutical composition contains a therapeutically effective amount of at least one compound described herein. The compounds of the present application can be combined with or diluted with a pharmaceutically acceptable excipient such as a carrier or diluent, or enclosed in a carrier in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions described herein are useful for treating diseases, disorders, and/or disorders modulated by the TRPV3 receptor.

In another aspect, the invention further provides for treating a disease modulated by a TRPV3 receptor in a subject by administering one or more compounds described herein effective to inhibit a TRPV3 receptor to a subject in need thereof, Methods of illness and/or disorder.

Also provided herein are methods of making the compounds described herein.

detailed description

The invention is defined by the scope of the claims, and not by the description provided below. The terms used in the scope of the appended claims are defined in the vocabulary section herein, but the terms of the scope of the patent application can be used in different ways, if otherwise explicitly stated.

The term "halogen" or "halo" means fluoro, chloro, bromo or iodo.

The term "alkyl" refers to a hydrocarbon chain radical having from 1 to 8 carbon atoms containing only carbon and hydrogen atoms and having no unsaturation, and is attached to the remainder of the molecule by a single bond, for example: methyl, Ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl). The term " _C1-6 alkyl" refers to an alkyl chain having from 1 to 6 carbon atoms. Unless otherwise stated or stated, all alkyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2- Butyl. Unless otherwise stated or stated, all alkenyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbyl group having from 2 to about 12 carbon atoms and having at least one carbon-carbon triple bond (groups having from 2 to about 10 carbon atoms are preferred). Non-limiting examples of alkynyl groups include ethynyl, propynyl and butynyl. Unless stated or stated to the contrary, all alkynyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen linkage. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ . Unless otherwise stated or stated, all alkoxy groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "cycloalkyl" denotes a non-aromatic monocyclic or polycyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged ring groups or spirobicyclic groups (eg, spiro(4,4)壬-2- base). Unless stated or stated to the contrary, all cycloalkyl groups described or protected herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a cyclic ring-containing group having from 3 to about 8 carbon atoms attached directly to an alkyl group. A cycloalkylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless stated or stated to the contrary, all cycloalkylalkyl groups described or protected herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to cyclic ring-containing groups having from 3 to about 8 carbon atoms having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless stated or stated to the contrary, all cycloalkenyl groups described or protected herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms, including monocyclic, bicyclic or tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. base. All aryl groups described or protected herein may be substituted or unsubstituted, unless stated or stated to the contrary.

The term "arylalkyl" means a direct bonded as above defined aryl radical as defined above in the alkyl group, e.g. -CH ₂ C ₆ H ₅ or _{-C 2 H 4 C 6 H 5} . Unless stated or stated to the contrary, all arylalkyl groups described or protected herein may be substituted or unsubstituted.

Unless otherwise specified, the term "heterocyclic ring" or "heterocyclyl" refers to a substituted or unsubstituted non-aromatic consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. 3-15 yuan ring base. The heterocyclic ring group may be a monocyclic, bicyclic or tricyclic ring system, and may include a fused ring system, a bridged ring system or a spiro ring system, and the nitrogen, phosphorus, carbon, oxygen or sulfur atom in the heterocyclic ring group may be Optionally oxidized to various oxidation states. Furthermore, the nitrogen atom may optionally be quaternized; moreover, unless the definition is otherwise limited, the heterocyclic ring or heterocyclic group may optionally contain one or more olefinic bonds. Examples of such heterocyclic ring groups include, but are not limited to, aza Base, azetidinyl, benzodioxolyl, benzodioxanyl, benzopyranyl, dioxolanyl, dioxaphospholyl, decahydroisoquine Polinyl, indanyl, porphyrin, isoindolyl, isochroman, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidine Base, oxadiazolyl, 2-oxooxazinyl, 2-oxoacridinyl, 2-oxopyrrolidinyl, 2-oxoaza Base, octahydroindenyl, octahydroisodecyl, perhydroaza Base, pyridazinyl, 4-acridone, pyrrolidinyl, acridinyl, phenothiazine, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyran A thiazoline group, a thiazolidinyl group, a thiomorpholinyl group, a thiomorpholinyl hydrazide, and a thiomorpholinyl hydrazine. A heterocyclic ring group can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable structure. Unless stated or stated to the contrary, all heterocyclyl groups described or protected herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring group attached directly to an alkyl group. The heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to give a stable structure. Unless stated or stated to the contrary, all heterocyclylalkyl groups described or protected herein may be substituted or unsubstituted.

Unless otherwise specified, the term "heteroaryl" refers to a substituted or unsubstituted 5-14 membered aromatic heterocyclic ring group having one or more heteroatoms independently selected from N, O or S. The heteroaryl group can be a monocyclic, bicyclic or tricyclic ring system. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable structure. Examples of such heteroaryl ring groups include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, fluorenyl, isodecyl, pyrrolyl, triazolyl, triazinyl, Tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzene And thienyl, benzopyranyl, oxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, porphyrinyl, naphthyridinyl, pteridinyl, fluorenyl, quin A morpholinyl group, a quinolyl group, an isoquinolyl group, a thiadiazolyl group, a pyridazinyl group, an acridinyl group, a phenazinyl group, and a pyridazinyl group. Unless stated or stated to the contrary, all heteroaryl groups described or protected herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical attached directly to an alkyl group. A heteroarylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure. Unless stated or stated to the contrary, all heteroarylalkyl groups described or protected herein may be substituted or unsubstituted.

The term "substituted" as used herein, unless otherwise specified, refers to a group or moiety having one or more substituents attached to the structural backbone of the group or moiety, including but not limited to: hydroxy, halo, Carboxyl, oxy, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or not Substituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero a cycloalkylalkyl ring, a substituted or unsubstituted heteroarylalkyl group, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted anthracene, -COOR ^x , -C(O)R ^x , -C(S) R ^x , -C(O)NR ^x R ^y , -C(O)ONR ^x R ^y , -NR ^x CONR ^y R ^z , -N(R ^x )SOR ^y , -N(R ^x )SO ₂ R ^y , -(=NN(R ^x )R ^y ), -NR ^x C(O)OR ^y , -NR ^x R ^y , -NR ^x C(O)R ^y , -NR ^x C(S)R ^y , -NR ^x C(S)NR ^y R ^z , -SONR ^x R ^y , -SO ₂ NR ^x R ^y , -OR ^x , -OR ^x C(O)NR ^y R ^z , -OR ^x C(O)OR ^y , -OC(O)R ^x , -OC(O)NR ^x R ^y , -R ^x NR ^y C(O)R ^z , -R ^x OR ^y , -R ^x C(O)OR ^y , -R ^x C(O)NR ^y R ^z , -R ^x C(O)R ^y , -R ^x OC(O)R ^y , -SR ^x , -SOR ^x , -SO ₂ R ^x and -ONO ₂ , wherein R ^x , R ^y and R ^{z are} independent Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl group, or substituted or unsubstituted heterocyclic ring.

The term "treatment" state, disorder or condition includes: (a) preventing or delaying the onset of a clinical condition of a condition, disorder or condition in which the state, disorder or condition is or susceptible to having the condition, disorder or condition. (c) inhibiting the state, disorder, or condition, ie, preventing or alleviating the disease, or at least one of its clinical or sub-therapies, in the subject but not yet undergoing or exhibiting clinical or subclinical symptoms of the state, disorder, or condition; Development of clinical symptoms; or (c) elimination of the disease, ie, causing the state, disorder or condition or at least one of its clinical or subclinical symptoms to subside.

The term "subject" includes mammals (especially humans) and other animals, such as livestock (eg, domestic pets, including cats, dogs) and non-live animals (such as wild animals).

"Therapeutically effective amount" refers to an amount of a compound that, when administered to a subject in need of a therapeutic state, disorder or condition, is sufficient to produce an effect on the subject being targeted for administration. A "therapeutically effective amount" will vary with the compound, the disease, its severity, and the age, weight, physical condition, and responsiveness of the subject to be treated.

The compounds described in the present invention can form salts. Non-limiting examples of pharmaceutically acceptable salts that form part of the invention include inorganic hydrazine derived salts, organic hydrazine salts, chiral guanidine salts, salts of natural amino acids, and salts of unnatural amino acids. With respect to all compounds of formula (I), the invention extends to its stereoisomeric forms and mixtures thereof. The various stereoisomeric forms of the invention may be separated from one another by methods known in the art, or may be obtained by stereospecific or asymmetric synthesis, as long as the prior art teaches the synthesis or isolation of particular stereoisomers. isomer. Tautomeric forms and mixtures of the compounds described herein are also contemplated.

Pharmaceutical composition

The pharmaceutical compositions of the present invention comprise at least one compound described herein and at least one pharmaceutically acceptable excipient such as a carrier or diluent. Preferably, the pharmaceutical composition contemplated comprises a compound described herein in an amount sufficient to inhibit the TRPV3 receptor in the subject.

Subjects considered include, for example, living cells and mammals including humans. The compounds of the invention may be combined with or diluted with a pharmaceutically acceptable excipient such as a carrier or diluent, or enclosed in a carrier in the form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, dextrin, carbonic acid Magnesium, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose low alkyl ether, citric acid, fatty acid, fatty acid amine, fatty acid single Glycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts which affect the osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents or Any combination of the above. The pharmaceutical compositions of the present invention may also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art.

The pharmaceutical compositions described herein can be prepared by conventional techniques known in the art. For example, the active compound may be mixed with the carrier or diluted in a carrier or enclosed in a carrier in the form of an ampule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as an excipient, excipient or medium for the active compound. The active compound can be adsorbed onto a granular solid container, such as in a sachet.

The pharmaceutical composition may be in a conventional form such as a capsule, a tablet, an aerosol, a solution, a suspension or a topically applied product.

The route of administration can be any route that effectively delivers the active compound of the invention to the appropriate or desired site of action. Suitable administration routes include, but are not limited to, oral administration, nasal administration, pulmonary administration, buccal administration, subdermal administration, intradermal administration, transdermal administration, parenteral administration. Medicine, rectal administration, depot administration, subcutaneous administration, intravenous administration, intraurethral administration, intramuscular administration, intranasal administration, ocular administration (eg use of ophthalmic solution) Or local administration (such as the use of topical ointment).

Solid oral preparation forms include, but are not limited to, tablets, capsules (soft gelatin or hard gelatin), dragees (containing active ingredients in powder or pellet form), troches and lozenges. Tablets, dragees or capsules having talc and/or carbohydrate carriers or binders and the like are especially suitable for oral use. Liquid preparations include, but are not limited to, syrups, emulsions, soft gelatin, and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions. For parenteral applications, injectable solutions or suspension formulations are especially suitable. It is preferably an aqueous solution having an active compound dissolved in polyhydroxylated castor oil.

Liquid preparations include, but are not limited to, syrups, emulsions, soft gelatin, and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions.

For parenteral use, injectable solutions or suspension formulations are especially suitable, preferably aqueous solutions with active compound in polyhydroxylated castor oil.

Suitable dosages of the compounds used to treat the diseases and disorders described herein can be determined by those skilled in the relevant art. The therapeutic dose is usually determined by a human dose range study based on prima facie evidence from animal studies. The dose must be sufficient to produce the desired therapeutic benefit without causing unwanted side effects. For example, the daily dose of the TRPV3 modulator can range from 0.1 mg/kg to about 30.0 mg/kg. Modes of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can be utilized and adjusted by those skilled in the art. All changes and modifications are considered to be within the scope of the invention.

treatment method

The invention provides compounds and pharmaceutical formulations thereof for use in the treatment of diseases, disorders and or disorders modulated by TRPV3. The invention further provides methods of treating a disease, disorder, and/or disorder modulated by TRPV3 in a subject by administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Diseases, disorders, and/or disorders that are thought to be modulated by TRPV3 include, but are not limited to, pain; nociceptive pain; toothache; heartache caused by ischemic myocardium; pain caused by migraine; acute pain; chronic pain; Neuropathic pain; postoperative pain; pain due to neuralgia (eg, postherpetic neuralgia or trigeminal neuralgia); pain due to diabetic neuropathy; toothache and cancer pain; inflammatory pain conditions (eg arthritis and Osteoarthritis); joint pain; neuropathy; neurodegenerative diseases; retinopathy; neuropathic skin disorders; stroke; bladder allergy; urinary incontinence; vulvodynia; gastrointestinal disorders, such as irritable bowel syndrome, stomach - esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease; inflammatory diseases such as pancreatitis; respiratory disorders, allergies and non- Allergic rhinitis, asthma or chronic obstructive pulmonary disease; irritation of the skin, eyes or mucous membranes; dermatitis; pruritus, such as uremia itch; fever; muscle spasm; Sputum; dyskinesia; depression; Huntington's disease; memory loss; brain function limitation; amyotrophic lateral sclerosis (ALS); dementia; arthritis; osteoarthritis; diabetes; obesity; urticaria; Keratocarcinoma; keratocanthoma; alopecia; Ménière's disease; tinnitus; hyperacusis; anxiety; and benign prostatic hyperplasia. Other diseases, disorders and/or disorders modulated by TRPV3 are described, for example, in WO2007/056124; Wissenbach, U. et al., Biology of the cell (2004), 96, 47-54; Nilius, B. et al., Physiol Rev (2007). ), 87, 165-217; Okuhara, DY, et al, Expert Opinion on Therapeutic Targets (2007), 11, 391-401; Hu, HZ et al, Journal of Cellular Physiology , (2006), 208, 201-212; In the cited references; all documents are hereby incorporated by reference in their entirety for their purposes.

General preparation method

The compounds described herein can be prepared using techniques known to those skilled in the art. Furthermore, the compounds described herein can be prepared by the reaction sequence described in Schemes 1-3 below. Further, in the following schemes, if specific hydrazines, acids, reagents, solvents, coupling agents and the like are mentioned, it should be understood that other suitable hydrazines, acids, reagents, solvents, etc. known in the art may also be used. Coupling agents and the like, and thus these are also included in the scope of the present invention. Variations in the reaction conditions (e.g., duration and/or temperature of the reaction) that are known in the art are also within the scope of the invention. All isomers of the compounds described in these schemes are also encompassed within the scope of the invention unless otherwise indicated.

The compound of the present invention represented by the general formula (I) can be produced as described in Scheme 1, wherein R ¹ , R ² , R ³ , R ⁴ , Q, X, m and n are as defined above. Thus, an intermediate of formula (1) (eg, 2-nitroaniline, 2-amino-3-nitropyridine, 4-amino-3-nitropyridine) in the presence of a suitable hydrazine Coupling with 2,3-dialkoxycinnamoquinone chloride of formula (2) produces the indoleamine of formula (3). The nitro group in the intermediate (3) is reduced using a reducing agent such as iron and acetic acid to form an intermediate of the formula (4). The intermediate (4) is cyclized to a benzimidazole derivative (5) by a dehydration reaction under a strong acidic reaction condition. Alternatively, a compound of formula (5) can be prepared by reductive cyclization of a compound of formula (3) using a reducing agent such as Raney nickel or iron and acetic acid. Copper (I) assisted coupling of (5) with the intermediate of formula (6) produces a compound of the invention represented by formula (I) wherein L is a leaving group such as a halogen. The compound of formula (I) wherein Q is a benzyl group can be prepared by direct alkylation of intermediate (5) with a benzyl halide in the presence of a strong base such as cesium carbonate. In some cases, the compound of formula (I) (when R ² is an alkyl group) can be selectively selected in the presence of a Lewis acid such as boron tribromide in dichloromethane or HBr in acetic acid. Dealkylation produces a compound of formula (Ia).

The compound of the formula (I) can also be produced by an alternative method as shown in Scheme 2, wherein R ¹ , R ² , R ³ , R ⁴ , Q, X, m and n are as defined above. In this method, the intermediate of formula (1a) is coupled to the intermediate of formula (6) prior to the cyclization step. Thus, the intermediate (1a) is treated with the intermediate (6) in the presence of a suitable hydrazine to give the coupled product (7), wherein preferably L is Cl, Br or I. Reduction of the nitro group of the intermediate (7) using a reducing agent such as iron and acetic acid to give the intermediate (8); in the presence of a suitable hydrazine, the intermediate (8) and the formula (2) The 2,3-dialkoxycinnamyl chloride is coupled to form the indoleamine of formula (9). The intermediate (9) is cyclized in the presence of a suitable acid such as acetic acid to form a compound of the invention represented by the formula (I).

Compounds of formula (I) can also be prepared as shown in Scheme 3, wherein R ¹ , R ² , R ³ , R ⁴ , Q, X, m and n are as previously described. Thus, in the presence of a suitable hydrazine, the intermediate of formula (10) is reacted with an amine of formula (11) to provide a compound of formula (7) wherein L is a halogen, preferably Cl or Br. Reduction of the nitro group of the intermediate (7) using a reducing agent such as iron and acetic acid to give the intermediate (8); in the presence of a suitable hydrazine, the intermediate (8) and the formula (2) The 2,3-dialkoxycinnamyl chloride is coupled to form the indoleamine of formula (9). The intermediate (9) is cyclized in the presence of a suitable acid such as acetic acid to form a compound of the invention represented by the formula (I).

The starting materials and reagents required for the synthesis of the intermediates and compounds of the invention are commercially available (e.g., Sigma-Aldrich) or can be prepared according to methods known to those skilled in the art or by methods available in the literature. In general, the compounds of the invention can be prepared by the following steps:

experiment

Unless otherwise stated, work-up means the operation of partitioning the reaction mixture between the organic phase and the aqueous phase, separating the layers, drying the organic layer with sodium sulfate, filtering, and evaporating the organic solvent. Purification, unless otherwise mentioned, means purification by gel chromatography techniques, typically using a polar compatible ethyl acetate/petroleum ether mixture as the mobile phase. The following abbreviations are used herein: DMSO- d ₆ : hexamethylene dimethyl hydrazine; DMF: N , N -dimethylformamide, J : coupling constant, in Hz; RT: room temperature (22-26 °C). Aq.: aqueous; AcOEt: ethyl acetate; equiv.: equivalent.

Preparation of intermediates

Intermediate 1

2-[( E )-2-(2-isopropoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole

Step 1: (2 E) -3- ( 2- isopropoxy-3-methoxyphenyl) - N - (2- nitrophenyl) acrylamide: at 0 ℃, to (2 E) -3-(2-Isopropoxy-3-methoxyphenyl)acrylic acid (5.0 g, 21.163 mmol) was added dropwise to a solution of dichloromethane (DCM) (50 ml). g, 31.752 mmol), and the reaction mixture was stirred at room temperature for 1 h. Excess grass chlorinated chlorine and solvent were distilled off under vacuum. The residue obtained was used directly in the next step.

Step 2: To a stirred solution of ruthenium chloride (5.4 g, 21.201 mmol) was added dropwise 2-nitroaniline (2.93 g, 21.213 mmol) in pyridine (50 ml) at rt. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into ice-cooled 10% hydrochloric acid (100 ml). The aqueous layer was extracted with ethyl acetate (2 × 100ml), the combined organic layer was washed with water (2 × 20ml), washed (100ml), brine and dried (Na ₂ SO _4). The crude product obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography to yield 4.83 g of product: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 ( d, J = 6.3 Hz, 6H), 3.85 (s, 3H), 4.52 (br s, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.13 - 7.22 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 8.13 (d, J = 15.9 Hz, 1H), 8.22 (d, J = 6.6 Hz, 1H), 8.93 (d, J = 7.5 Hz, 1H), 10.64 (br s, 1H).

Step 3: (2 E) - N - (2- aminophenyl) -3- (2-isopropoxy-3-methoxyphenyl) acrylamide: To a solution of Intermediate Step 2 (4.0g, 11.224 mmol) An aqueous solution of ammonium chloride (6.0 g, 112.17 mmol) was added to a stirred solution in ethanol. The reaction mixture was refluxed for 20 min, then iron powder (1.88 g, 33.667 mmol) was added portionwise over 30 min and then further refluxed for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (EtOAc) The ethyl acetate layer was washed with water (2 × 50ml), brine (50ml), dried (Na ₂ SO _4), filtered, and concentrated to yield 3.5g white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 1.29 ( d, J = 6.9 Hz, 6H), 3.83 (s, 3H), 4.45 (br s, 1H), 5.08 (br s, 2H), 6.60 (d, J = 15.6 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 HZ, 1H), 7.59 (s, 1H), 8.07 (d, J = 15.6 Hz, 1H), 9.25 (s, 1H).

Step 4: 2-[( E )-2-(2-Isopropoxy-3-methoxyphenyl)ethenyl]-1 H -benzimidazole: intermediate of step 3 above (3.4 g, 10.147 Methyl) was dissolved in glacial acetic acid (34 mL). Excess acetic acid was distilled off under reduced pressure, and the reaction mixture was slightly made basic using aqueous sodium carbonate. The reaction mixture was washed with water (2 × 50ml) with ethyl acetate (100ml), washed with brine (50ml), dried over Na ₂ SO _4. The crude product obtained by evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to afford 2.84 g of pale white solid product as of EtOAc (EtOAc: EtOAc) , 1108, 745cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.22 (d, J = 6.6 Hz, 6H), 3.79 (s, 3H), 4.44 (br s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.17-7.23 (m, 3H), 7.54 - 7.62 (m, 3H), 7.86 (d, J = 16.8 Hz, 1H); ESI-MS ( m/z ) 309.22 (M+H) ⁺ .

Intermediate 2-31 was prepared according to the procedure described for the intermediate 1 by using the appropriate 2-nitroaniline and Cinnamonium chloride. Structural details and characterization data are given in Table 1.

It can be noted that the above asymmetrically substituted benzimidazole intermediates substituted on imidazole nitrogen (e.g., intermediates 13-16, 26, 27, 28) produce a regioisomeric product mixture. To overcome this problem, the compounds of the invention are also prepared from acrylamide derivatives such as intermediate 32. A synthesis method for producing a acrylamide derivative of the formula (9) wherein R ¹ , R ² , R ³ , R ⁴ , Q, X, m and n are as defined above is given below.

Intermediate 32

(2 E )-N-{4-chloro-2-[(5-cyanopyridin-2-yl)amino]phenyl}-3-[3-methoxy-2-(2-methylpropane) Oxy)phenyl]prop-2-enylamine

Step 1: 6-[(5-Chloro-2-nitrophenyl)amino]nicotinonitrile: To 5-chloro-2-nitroaniline (2.0 g, 11.0 mmol) in dry N , N -dimethyl To a well-stirred solution of acetamide (DMA; 15 ml), cesium carbonate (Cs ₂ CO ₃ ; 75 mg, 2.3 mmol) and 6-chloronicotinonitrile (193 mg, 1.3 mmol) were added, and the reaction mixture was heated at 130 ° C. 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2 × 100ml), and washed with water (2 × 50ml), brine (20ml), dried (Na ₂ SO _4), filtered and reduced pressure Concentration gave 2.5 g of product.

Step 2: 6-[(2-Amino-5-chlorophenyl)amino] Nicotinonitrile: Add chlorination to a stirred solution of the intermediate of Step 1 (2.5 g, 9.1 mmol) in ethanol (45 mL) An aqueous solution of ammonium (4.87 g, 91.0 mmol) was added and the reaction mixture was refluxed at 100 °C. After 15 min, iron powder (1.5 g, 27 mmol) was added portionwise to the reaction mixture and further refluxed for 2 h. After completion of the reaction, excess ethanol was distilled off under reduced pressure; the mixture was diluted with chloroform (200 ml) and filtered over a bed of celite. The combined organic layer was washed with water (2 × 50ml) and brine, dried (Na ₂ SO _4), filtered and concentrated under reduced pressure to give 1.8g of product.

Step 3: (2 E) - N - {4- chloro-2 - [(5-cyano-pyridin-2-yl) amino] phenyl} -3- (2-isobutoxy-3-methoxy phenyl) acrylamide: 3- (2-isobutoxy-3-methoxyphenyl) acrylic acid (613mg, 2.4mmol) was stirred in DCM (10ml) to (2 E) was sufficient Grass chloroform (613 mg, 2.4 mmol) was added dropwise while a few drops of dimethylformamide (DMF) were added. The reaction mixture was stirred at room temperature for 3 h to give the corresponding chlorobenzene, and excess DCM was evaporated from this chlorobenzene under reduced pressure. To a solution of the intermediate (500 mg, 2 mmol) in EtOAc (EtOAc) After completion of the reaction, water (20ml) the reaction mixture was diluted, and extracted with ethyl acetate (2 × 50ml), washed the combined organic layers were washed with water (2 × 20ml) and brine, dried (Na ₂ SO _4), filtered, and Concentration under reduced pressure gave 215 mg of product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.04 (d, J = 6.3 Hz, 6H), 2.06-2.15 (m, 1H), 3.74 (d, J = 6.6 Hz, 2H), 3.86 (s, 3H) , 6.53 (d, J = 15.6 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 6.9 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.83 (s , 2H), 8.11 (d, J = 15.6 Hz, 1H), 8.45 (s, 1H).

Intermediates 33-38 were prepared from the procedure described for intermediate 32 by using the appropriate 2-nitroaniline, 6-chloronicotinonitrile and 2,3-dialkoxycinnamic acid derivatives. The structure and characterization data for these intermediates are given in Table 2.

Inter-body 39-55 was prepared according to the procedure described in Scheme 3 by using the appropriate aminopyridine and chloro-3-nitropyridine and the following 2,3-dialkoxy cinnamic acid derivatives:

Intermediate 39

(2 E )-N-{2-[(5-Cyanopyridin-2-yl)amino]pyridin-3-yl}-3-[2-(cyclopentyloxy)-3-methoxybenzene Prop-2-amine

Step 1: 6-[(3-Nitropyridin-2-yl)amino]nicotinonitrile: Add to a stirred solution of 6-amino nicotinonitrile (0.631 g, 5.29 mmol) in dry DMA (15 mL) Cs ₂ CO ₃ (2.157 g, 6.62 mmol) and 2-chloro-3-nitropyridine (0.700 g, 4.415 mmol), and the reaction mixture was heated at 80 ° C for 24 h under nitrogen atmosphere. Upon completion, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2 × 100ml), and washed with water (2 × 50ml) and brine, dried (Na ₂ SO _4), filtered and concentrated under reduced pressure to give 543 mg of product.

Step 2: 6-[(3-Aminopyridin-2-yl)amino]nicotinonitrile: Ammonium chloride was added to the solution of the intermediate of Step 1 (500 mg, 2.202 mmol) in ethanol (5 ml). 1.178 g, 22.026 mmol) of an aqueous solution, and the reaction mixture was heated to 90-100 °C. Iron powder was then added to the reaction mixture in portions and further refluxed for 2 h. After completion of the reaction, the reaction mixture was diluted with chloroform (100 ml) and filtered. The filtrate was washed with a minimum amount of water, brine (25ml), dried over Na ₂ SO ₄ and concentrated to give 423mg of product.

Step 3: To a stirred solution of (2 E) -3- [2- (cyclopentyloxy) -3-methoxyphenyl] acrylic acid (300mg, 1.144mmol) in DCM (5ml) and after sufficiently cooled solution Grass chloroform (218 mg, 1.716 mmol) was added dropwise while a few drops of DMF were added. Then, the reaction mixture was stirred at room temperature for 4 h, and the solvent was evaporated under reduced pressure. A solution of the intermediate of Step 2 (218 mg, 1.030 mmol) in pyridine (5 mL) was then evaporated. After completion of the reaction, the reaction mixture was washed with water (50ml), and extracted with ethyl acetate (3 × 25ml), then the combined organic layers were washed with water (2 × 20ml), washed with brine (50ml) and dried (Na ₂ SO ₄ ). The crude product obtained after evaporation of the solvent under reduced pressure was purified by recrystallization to yield 312 g. ¹ H NMR data (300 MHz, DMSO- d ₆ ) δ 1.58-1.68 (m, 4H), 1.73-1.79 (m, 4H), 3.82 (s, 3H), 4.87 (br s, 1H), 6.86 (d) , J =15.6 Hz, 1H), 7.13-7.23 (m, 4H), 7.88-7.93 (m, 2H), 8.05-8.12 (m, 2H), 8.18 (br s, 1H), 8.63 (br s, 1H), 9.55 (br s, 1H), 9.96 (br s, 1H).

Intermediates 40-55 were prepared by the procedure described in Intermediate 39. The structure and characterization data for these intermediates are given in Table 3.

The invention will be illustrated by the following examples, but the invention is not limited to the following examples.

Example

Example 1

2-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-1-pyridin-2-yl-1 H -benzimidazole

Add Cs ₂ CO ₃ (407 mg, 1.250 mmol) and cuprous iodide (CuI; 24 mg, 0.125) to a solution of Intermediate 5 (200 mg, 0.625 mmol) in dry DMA (3 mL). Methyl) and 2-iodopyridine (192 mg, 0.937 mmol). The reaction mixture was stirred at 130 ° C for 5 h under nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (10 ml) and then ethyl acetate (2×10 ml). The combined organic layers were washed with water (2 × 30ml), washed (30ml) with brine and dried (Na ₂ SO _4). The crude product obtained after the solvent was distilled off under reduced pressure, using petroleum ether in 20% ethyl acetate, the crude product was purified by silica gel column chromatography, an off-white solid product 42mg ^{generated; 1 H NMR (300 MHz,} CDCl 3) δ 0.15-0.25 (m, 2H), 0.42-0.50 (m, 2H), 0.87 (br s, 1H), 3.78 (d, J = 7.2 Hz, 2H), 3.83 (s, 3H), 6.85 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 7.05-7.12 (m, 1H), 7.30-7.50 (m, 6H), 7.82-7.88 (m, 1H), 7.97 (t, J = 6.6 Hz, 1H), 8.20-8.30 (m, 1H), 8.70-8.80 (m, 1H); ESI-MS ( m/z ) 398.87 (M+H) ⁺ .

Example 2

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-pyridin-2-yl-1 H -benzimidazole

Intermediate 6 (300 mg, 0.898 mmol) and 2-bromopyridine (212 mg, 1.347 mmol) were taken in dry DMA (5 mL) in EtOAc (3 mL). prepare the coupling _{Cs 2 CO 3 (585mg, 1.794mmol} ) of the compound, to generate off-white solid ^{104mg; 1 H NMR (300 MHz,} CDCl 3) δ 1.61-1.75 (m, 8H), 3.83 (s, 3H) , 4.82 (br s, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.98 (t, J = 7.8 Hz, 2H), 7.07 (d, J = 7.5 Hz, 1H), 7.21 - 7.33 (m , 3H), 7.39-7.47 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.91-7.97 (m, 1H), 8.13 (d, J = 16.2 Hz, 1H), 8.70-8.76 ( m, 1H); APCI-MS ( m/z ) 412.27 (M+H) ⁺ .

Example 3

1-(5-chloropyridin-2-yl)-2-{( E )-2-[2-(cyclopentyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazole

Intermediate 6 (400 mg, 1.197 mmol) and 2,5-dichloropyridine (266 mg, 1.796 mmol) in dry DMA (5 mL) as described in Example 1 in dry DMA (5 mL) This compound was prepared by coupling with Cs ₂ CO ₃ (780 mg, 2.395 mmol) to give 214 mg of product as an off white solid; IR (KBr) 2964, 1574, 1471, 1287, 1017, 745 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 8H), 3.84 (s, 3H), 4.85 (br s, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.99 (t, J = 8.4 Hz , 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.26-7.32 (m, 2H), 7.39-7.48 (m, 3H), 7.85 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 15.0 Hz, 1H), 8.68 (s, 1H); APCI-MS ( m/z ) 446.27 (M+H) ⁺ .

Example 4

2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1-(5-nitropyridin-2-yl)-1 H -benzo Imidazole

Intermediate 6 (200 mg, 0.598 mmol) in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (390 mg, 1.197 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. 2-chloro-5-nitropyridine (189mg, 0.898mmol) coupling title compound was prepared, 80mg generated off-white ^{solid; IR (KBr) 2959,1601,1525,1465,1265,749 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.70-1.80 (m, 8H), 3.86 (s, 3H), 4.88 (br s, 1H), 6.89 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.08-7.15 (m, 1H), 7.26-7.33 (m, 1H), 7.36-7.40 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 15.9 Hz, 1H), 8.72 (dd, J = 2.4, 8.7 Hz, 1H), 9.56 (s, 1H); APCI-MS ( m/z ) 457.17 (M+H) ⁺ .

Example 5

2-[( E )-2-(2-benzyloxy-3-methoxyphenyl)vinyl]-1-(3,5-dichloropyridin-2-yl)-1 H -benzimidazole

Intermediate 7 (200 mg, 0.567 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (365 mg, 1.189 mmol) and CuI (21 mg, 0.118 mmol) as described in Example 1. , 3,5-trichloro-pyridine (153mg, 0.841mmol) coupling title compound was prepared, 109mg generated off-white ^{solid; IR (KBr) 2934,1601,1454,1268,1070,741cm -1;} 1 H NMR (300 MHz, CDCl ₃ ) δ 3.83 (s, 3H), 4.92 (s, 2H), 6.80-6.88 (m, 1H), 6.96-7.04 (m, 4H), 7.12-7.20 (m, 1H), 7.27-7.36 (m, 6H), 7.75-7.83 (m, 2H), 7.89 (d, J = 16.2 Hz, 1H), 8.33 (s, 1H); ESI-MS ( m/z ) 502.53 (M+H) ⁺ .

Example 6

1-(3,5-Dichloropyridin-2-yl)-2-{( E )-2-[2-(2-fluorobenzyloxy)-3-methoxyphenyl]vinyl}-1 H -benzimidazole

Intermediate 8 (200 mg, 0.574 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (373 mg, 1.149 mmol) and CuI (28 mg, 0.149 mmol) as described in Example 1. , 3,5-trichloro-pyridine (156mg, 0.862mmol) coupling title compound was prepared, 36mg generated off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 3.82 (s, 3H), 5.01 (s, 2H ), 6.85-7.12 (m, 9H), 7.27-7.33 (m, 1H), 7.45 (t, J = 6.0 Hz, 1H), 7.82 (s, 2H), 7.89 (d, J = 15.9 Hz, 1H) , 8.41 (s, 1H); ESI-MS ( m/z ) 521.32 (M+H) ⁺ .

Example 7

2-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 6 (200 mg, 0.598 mmol) in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (390 mg, 1.198 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. with 2-chloro-nicotinonitrile (100mg, 0.718mmol) coupling title compound was prepared, 82mg generated off-white ^{solid; IR (KBr) 2936,2233,1628,1580,1455,1266,741cm -1;} 1 H NMR (300 _{MHz, CDCl 3) δ 1.68-1.80 (} m, 8H), 3.84 (s, 3H), 4.80 (br s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.98-7.09 (m, 3H) , 7.18 (d, J = 7.8 Hz, 1H), 7.26-7.39 (m, 2H), 7.61-7.68 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.90 (d, J =15.9) Hz, 1H), 8.27 (d, J = 6.3 Hz, 1H), 8.95 (s, 1H); APCI-MS ( m/z ) 437.50 (M+H) ⁺ .

Example 8

6-{2-[( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 2 (200 mg, 0.621 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (405 mg, 1.243 mmol) and CuI (23 mg, 0.124 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (129mg, 0.931mmol), and generates an off-white solid product ^{97mg; IR (KBr) 2957,2229,1591,1475,1266,1073,735 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 0.92 (t, J = 7.2 Hz, 3H), 1.35-1.47 (m, 2H), 1.63-1.73 (m, 2H), 3.85 (s, 3H), 3.96 (t, J = 6.6 Hz) , 2H), 6.87 (d, J = 7.8 Hz, 1H), 6.99-7.09 (m, 2H), 7.28-7.38 (m, 3H), 7.52 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.19 (d, J = 6.3 Hz, 1H), 8.98 (s, 1H); ESI-MS ( m/z ) 425.17 (M+H) ⁺ .

Example 9

6-{2-[( E )-2-(2-isopropoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 1 (200 mg, 0.649 mmol) and 6 in dry DMA (4 ml) in the presence of Cs ₂ CO ₃ (423 mg, 1.298 mmol) and CuI (25 mg, 0.129 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (135mg, 0.973mmol), and generates an off-white solid product ^{30mg; IR (KBr) 2977,2233,1590,1461,1286,1083,770 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.28 (d, J = 6.6 Hz, 6H), 3.84 (s, 3H), 4.50 (br s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.28-7.37 (m, 3H), 7.51 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H) , 7.82 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 16.2 Hz, 2H), 8.99 (s, 1H); ESI-MS ( m/z ) 411.28 (M+H) ⁺ .

Example 10

6-{2-[( E )-2-(2-(1-Ethylpropoxy)-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 4 (200 mg, 0.645 mmol) was obtained in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (420 mg, 1.290 mmol) and CuI (24.57 mg, 0.129 mmol) as described in Example 1 the title compound was prepared coupling of 6-chloro-nicotinonitrile (135mg, 0.967mmol), and generates an off-white solid product ^{57mg; IR (KBr) 2960,2235,1588,1478,1268,1069,737 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 0.89 (t, J = 6.3 Hz, 6H), 1.50-1.56 (m, 4H), 3.78 (s, 3H), 4.16 (br s, 1H), 7.01 (br s, 2H) ), 7.22-7.32 (m, 4H), 7.50 (d, J = 6.3 Hz, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 8.11 (d) , J =16.2 Hz, 1H), 8.65 (d, J = 7.8 Hz, 1H), 9.21 (s, 1H); APCI-MS ( m/z ) 439.20 (M+H) ⁺ .

Example 11

6-(2-{( E )-2-[3-methoxy-2-(2-methylpropoxy)phenyl]ethenyl}-1 H -benzimidazol-1-yl)pyridine- 3-nitrile

By intermediate 3 (200 mg, 0.675 mmol) in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (440 mg, 1.350 mmol) and CuI (25.71 mg, 0.135 mmol) as described in Example 1 the title compound was prepared coupling of 6-chloro-nicotinonitrile (140mg, 1.012mmol) generates 123mg off-white ^{solid; IR (KBr) 2957,2226,1588,1480,1266,1071,747 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 0.97 (d, J = 6.9 Hz, 6H), 1.90-1.96 (m, 1H), 3.70 (d, J = 6.3 Hz, 2H), 3.81 (s, 3H), 7.06 ( s, 2H), 7.26-7.37 (m, 4H), 7.55 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 16.2 Hz, 1H), 8.68 (d, J = 7.8 Hz, 1H), 9.24 (s, 1H); APCI-MS ( m/z ) 425.28 (M+H) ⁺ .

Example 12

6-{2-[( E )-2-(2-[cyclopropylmethoxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 5 (200 mg, 0.625 mmol) and 6 in dry DMA (3 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.250 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (130mg, 0.937mmol), and generates an off-white solid product ^{62mg; IR (KBr) 2927,2227,1735,1589,1474,1267,980 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 0.21 (d, J = 4.8 Hz, 2H), 0.49 (d, J = 7.5 Hz, 2H), 0.88 (br s, 1H), 3.81-3.88 (m, 5H), 6.89 (d, J = 7.8 Hz, 1H), 7.02-7.12 (m, 2H), 7.30-7.40 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 9 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.7 Hz, 2H), 9.02 (br s, 1H); ESI-MS ( m/z ) 423.27 (M+H) ⁺ .

Example 13

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 6 (200 mg, 0.598 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (390 mg, 1.196 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (124mg, 0.898mmol), and generates an off-white solid product ^{43mg; 1 H NMR (300 MHz,} CDCl 3) δ 1.50-1.57 (m, 2H), 1.64-1.70 (m, 2H ), 1.76-1.83 (m, 4H), 3.86 (s, 3H), 4.89 (br s, 1H), 6.89 (d, J = 6.3 Hz, 1H), 6.98-7.04 (m, 1H), 7.10 (d) , J = 7.2 Hz, 1H), 7.24 - 7.29 (m, 1H), 7.31 (d, J = 15.3 Hz, 1H), 7.34 - 7.42 (m, 1H), 7.54 (d, J = 6.0 Hz, 1H) , 7.64 (d, J = 6.3 Hz, 1H), 7.84 (d, J = 6.0 Hz, 1H), 8.15 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 9.00-9.07 (m, 1H); ESI-MS ( m/z ) 437.35 (M+H) ⁺ .

Example 14

6-(2-{( E )-2-[2-(2-Fluorobenzyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl)nicotinonitrile

Intermediate 8 (200 mg, 0.574 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (373 mg, 1.149 mmol) and CuI (28 mg, 0.149 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (118mg, 0.862mmol), and generates an off-white solid product ^{32mg; 1 H NMR (300 MHz,} CDCl 3) δ 3.87 (s, 3H), 5.06 (s, 2H), 6.89- 7.00 (m, 2H), 7.06-7.12 (m, 3H), 7.27-7.39 (m, 3H), 7.46-7.55 (m, 4H), 7.80 (d, J = 7.8 Hz, 1H), 7.96-8.06 ( m, 2H), 8.80 (s, 1H); ESI-MS ( m/z ) 477.53 (M+H) ⁺ .

Example 15

6-{2-[( E )-2-(2-(2-Cyanobenzyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 9 (200 mg, 0.524 mmol) was obtained in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (342.5 mg, 1.048 mmol) and CuI (20 mg, 0.104 mmol) as described in Example 1 the title compound was prepared coupling of 6-chloro-nicotinonitrile (109.20mg, 0.787mmol), and generates an off-white solid product ^{83mg; IR (KBr) 2937,2233,1592,1476,1389,1268,1072 cm -1} ; 1 H NMR ( 300 MHz, CDCl ₃ ) δ 3.83 (s, 3H), 5.20 (s, 2H), 7.11-7.15 (m, 2H), 7.23-7.35 (m, 4H), 7.52-7.58 (m, 2H), 7.72 7.83 (m, 4H), 7.91 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 16.2 Hz, 1H), 8.61 (d, J = 8.1 Hz, 1H), 9.16 (s, 1H); APCI-Ms ( m/z ) 484.13 (M+H) ⁺ .

Example 16

6-{2-[( E )-2-(3-methoxy-2-{[2-(trifluoromethyl)benzyl]oxy}phenyl)vinyl]-1 H -benzimidazole -1-yl}nicotinonitrile

Intermediate 10 (200 mg, 0.471 mmol) was obtained in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (308 mg, 0.943 mmol) and CuI (17.96 mg, 0.094 mmol) as described in Example 1. 6-chloro-nicotinonitrile (98mg, 0.707mmol) coupling title compound was prepared, 109mg generated off-white ^{solid; IR (KBr) 2944,2234,1591,1479,1315,1094,744 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 3.83 (br s, 3H), 5.14 (s, 2H), 7.14 (d, J = 6.3 Hz, 2H), 7.27-7.37 (m, 5H), 7.53-7.59 (m, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 15.6 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H) , 9.10 (s, 1H); APCI-MS ( m/z ) 527.22 (M+H) ⁺ .

Example 17

6-(2-{( E )-2-[2-(2,6-Difluorobenzyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl) Nicotinonitrile

Intermediate 11 (201 mg, 0.509 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (333 mg, 1.019 mmol) and CuI (20 mg, 0.101 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (106mg, 0.764mmol), and generates an off-white solid product ^{86mg; IR (KBr) 2968,2231,1591,1471,1388,1264,1060,728 cm- 1} ; 1 H NMR ( 300 MHz, CDCl ₃ ) δ 3.84 (s, 3H), 5.11 (s, 2H), 7.00 (t, J = 7.8 Hz, 2H), 7.05-7.12 (m, 2H), 7.17-7.22 (m, 2H) , 7.28-7.41 (m, 3H), 7.57 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 15.9 Hz, 1H), 8.65 (dd, J = 1.8, 8.4 Hz, 1H), 9.20 (s, 1H); APCI-MS ( m/z ) 495.12 (M+H) ⁺ .

Example 18

6-(2-{( E )-2-[2-(2,4-difluorobenzyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl) Nicotinonitrile

Intermediate 12 (200 mg, 0.52 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (345 mg, 1.05 mmol) and CuI (20 mg, 0.10 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (110mg, 0.79mmol) and 95mg generating off-white ^{solid; IR (KBr) 2940,2231,1589,1478,1387,1269,1072,740 cm -1} ; 1 H NMR ( 300 MHz, DMSO- d ₆ ) δ 3.85 (s, 3H), 5.04 (s, 2H), 7.04-7.13 (m, 3H), 7.16-7.25 (m, 3H), 7.28-7.38 (m, 2H), 7.49-7.57 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 15.9 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 9.18 (s, 1H); ESI-MS ( m/z ) 495.01 (M+H) ⁺ .

Example 19

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)ethenyl]-1 H -benzoimidazole-1-yl}pyridazine-3- Ethyl carboxylate

Intermediate 6 (200 mg, 0.598 mmol) and 6 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (890 mg, 1.19 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. Coupling of chloropyridazine-3-carboxylate (168 mg, 0.898 mmol) gave the title compound. The solvent was evaporated under reduced pressure to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssss , 1268, 1150 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.70 (m, 8H), 1.78-1.85 (m, 5H), 3.86 (s, 3H), 4.87 (br s, 1H) ), 6.89 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.26-7.42 (m, 3H), 7.59 (d) , J = 7.8 Hz, 1H), 7.86 (t, J = 8.1 Hz, 2H), 8.24 (d, J = 15.9 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H); APCI-MS ( m /z ) 485.48(M+H) ⁺ .

Example 20

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)ethenyl]-1 H -benzoimidazole-1-yl}pyridazine-3- Nitrile

Step 1: (6-{2-[( E )-2-(2-[Cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}哒Pyrazin-3-yl)carboxylic acid: by the method of Example 19, 6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]- An aqueous solution of lithium hydroxide (35 mg, 0.826 mmol) was added to a solution of ethyl 1H -benzimidazol-1-yl}pyridazine-3-carboxylate (200 mg, 0.413 mmol). This compound was prepared by stirring the reaction mixture at room temperature for 2 h. After the reaction was completed, the reaction mixture was crystallised from EtOAc EtOAc (EtOAc)

Step 2: 6-{2-[( E )-2-(2-[Cyclopentyloxy]-3-methoxyphenyl)ethenyl]-1 H -benzimidazol-1-yl}pyridazine Benzylamine: This compound was prepared by the addition of triethylamine (66.44 mg, 0.657 mmol) to EtOAc (EtOAc) Ethyl chloroformate (71.40 mg, 0.657 mmol) was added to the reaction mixture cooled to -10 ° C. After 30 min, aqueous ammonia (2 ml, 25%) was added and the mixture was stirred for 30 min. The reaction mixture was quenched with EtOAc EtOAc m.

Step 3: Add triethylamine (80.0 mg, 0.78 mmol) and three to a stirred solution of the product from Step 2 (121 mg, 0.263 mmol) in dry DCM (5 mL). The fluoroacetic anhydride (84 mg, 0.395 mmol) was stirred for a further 1 h to give the final compound. The reaction mixture was then extracted with CHCl _3, the combined organic layer was then washed with water, brine, dried (Na ₂ SO _4), filtered and concentrated in vacuo. Use in 2% acetone in chloroform, the crude product was purified by silica gel column chromatography, an off-white solid product 79mg ^{generated; IR (KBr) 2959,2243,1573,1455,1263,743 cm -1} ; 1 H NMR (300 MHz, DMSO - d ₆ ) δ 1.62-1.68 (m, 4H), 1.78-1.89 (m, 4H), 3.86 (s, 3H), 4.89 (br s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.23-7.28 (m, 1H), 7.35-7.44 (m, 2H), 7.59 (d, J = 7.8 Hz) , 1H), 7.87 (d, J = 9.3 Hz, 2H), 8.06 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 15.9 Hz, 1H); APCI-MS ( m/z ) 438.21 ( M+H) ⁺ .

Example 21

2-{( E )-2-[2-(cyclopentyloxy)-3-methoxyphenyl]ethenyl}-1-pyrimidin-2-yl-1 H -benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (391 mg, 1.197 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. - chloropyrimidine (103mg, 0.898mmol) coupling title compound was prepared, 73mg generated off-white ^{solid; IR (KBr) 2950,1568,1421,1266,1065 cm -1} ; 1 H NMR (300 MHz, CDCl 3) δ 1.67-1.73(m,4H),1.76-1.88(m,4H),3.87(s,3H),4.88(br s,1H),6.88(d, J =7.8 Hz,1H),7.04(t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 7.32 - 7.36 (m, 3H), 7.83 (d, J = 6.6 Hz, 1H), 8.02 (d, J = 16.2 Hz, 1H), 8.16 (d) , J = 7.8 Hz, 1H), 8.25 (d, J = 15.6 Hz, 1H), 8.92 (d, J = 4.2 Hz, 1H); ESI-MS ( m/z ) 413.19 (M+H) ⁺ .

Example 22

1-(5-Bromopyrimidin-2-yl)-2-{( E )-2-[2-(1-ethylpropoxy)-3-methoxyphenyl]ethenyl}-1 H - Benzimidazole

Intermediate 4 (500 mg, 1.492 mmol) and 5 in dry DMA (10 ml) in the presence of Cs ₂ CO ₃ (973 mg, 2.985 mmol) and CuI (57 mg, 0.298 mmol) as described in Example 1. - bromo-2-chloropyrimidine (434mg, 2.238mmol) coupling title compound was prepared, 380mg generated off-white ^{solid; IR (KBr) 2922,1560,1417,1259,1088,746 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.95 (d, J = 7.2 Hz, 6H), 1.63-1.69 (m, 4H), 3.85 (s, 3H), 4.20 (br s, 1H), 6.87 (d, J = 8.1 Hz , 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.20-7.26 (m, 1H), 7.31-7.37 (m, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 15.9 Hz, 1H), 8.93 (s, 2H); APCI-MS ( m/z ) 493.41 (M ) ⁺ .

Example 23

1-(5-bromopyrimidin-2-yl)-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) was obtained in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (391 mg, 1.197 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. Coupling of 5-bromo-2-chloropyrimidine (174 mg, 0.898 mmol) gave the title compound. The crude product was purified by silica gel column chromatography using 12% ethyl acetate in petroleum ether to yield 175 mg of pale white solid product: IR (KBr) 2957, 2233, 1589, 1477, 1267, 1068, 738 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.70 (m, 4H), 1.89-1.96 (m, 4H), 3.87 (s, 3H), 4.87 (br s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.20-7.26 (m, 1H), 7.29-7.39 (m, 2H), 7.82 (d, J = 7.5 Hz, 1H), 7.96 (d, J =15.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 16.2 Hz, 1H), 8.93 (s, 2H); APCI-MS ( m/z ) 491.41 (M) ⁺ .

Example 24

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-[3-(trifluoromethyl)pyridin-2-yl]-1 H - Benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (390 mg, 1.197 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. - chloro-3- (trifluoromethyl) pyridine the title compound was prepared conjugate (163mg, 0.898mmol) generates 83mg off-white ^{solid; IR (KBr) 2959,1591,1456,1267,1031,741 cm -1} ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.50-1.75 (m, 8H), 3.81 (s, 3H), 4.89 (br s, 1H), 6.63 (d, J = 15.0 Hz, 1H), 6.79-6.89 ( m, 2H), 6.95 (d, J = 6.3 Hz, 2H), 7.12-7.18 (m, 1H), 7.29 (t, J = 6.3 Hz, 1H), 7.55-7.65 (m, 1H), 7.79 (d) , J = 7.5 Hz, 1H), 7.86 (d, J = 15.3 Hz, 1H), 8.24 (d, J = 6.0 Hz, 1H), 8.88-8.93 (m, 1H); ESI-MS ( m/z ) 480.51 (M+H) ⁺ .

Example 25

2-[( E )-2-(2-isopropoxy-3-methoxyphenyl)vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzo Imidazole

Intermediate 1 (200 mg, 0.649 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (418 mg, 1.282 mmol) and CuI (25 mg, 0.129 mmol) as described in Example 1. Coupling of -5-chloro-5-(trifluoromethyl)pyridine (177 mg, 0.972 mmol) afforded the title compound ield ^{. 1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.23 (d, J = 6.3 Hz, 6H), 3.83 (s, 3H), 4.49 (br s, 1H), 6.85 (d, J = 7.8 Hz, 1H ), 7.00 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.26-7.35 (m, 3H), 7.47 (d, J = 8.4 Hz, 1H), 7.62 (d) , J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 15.9 Hz, 2H), 8.99 (s, 1H); ESI-MS ( m/z ) 454.20 ( M+H) ⁺ .

Example 26

2-[( E )-2-(2-cyclopropoxy-3-methoxyphenyl)vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzo Imidazole

Intermediate 5 (170 mg, 0.531 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (346 mg, 1.062 mmol) and CuI (20 mg, 0.106 mmol) as described in Example 1. - the title compound was prepared conjugate chloro-5-trifluoromethyl-pyridine (145mg, 0.796mmol) generates 98mg off-white ^{solid; IR (Neat) 2943,1601,1451,1269,1125,1080,988 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.18-0.26 (m, 2H), 0.44-0.52 (m, 2H), 1.15 (br s, 1H), 3.81 (d, J = 5.4 Hz, 2H), 3.85 (s, 3H), 6.87 (d, J = 6.3 Hz, 1H), 7.03 (t, J = 6.0 Hz, 1H), 7.10 (d, J = 6.0 Hz, 1H), 7.26-7.31 (m, 1H) , 7.36-7.44 (m, 2H), 7.53 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 6.3 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 8.15-8.24 ( m, 2H), 9.02 (s, 1H); ESI-MS ( m/z ) 466.18 (M+H) ⁺ .

Example 27

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1 H - Benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (389 mg, 1.196 mmol) and CuI (22 mg, 0.119 mmol) as described in Example 1. - chloro-5- (trifluoromethyl) pyridine the title compound was prepared conjugate (217mg, 1.196mmol) generates 110mg off-white ^{solid; IR (KBr) 2951,1605,1474,1325,1133,735 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.15-1.25 (m, 4H), 1.35-1.42 (m, 4H), 3.78 (s, 3H), 4.48 (br s, 1H), 6.90-7.04 (m, 3H), 7.15-7.23 (m, 2H), 7.32-7.42 (m, 3H), 7.76-7.88 (m, 3H), 8.81 (s, 1H); ESI-MS ( m/z ) 454.10 (M+H ) ⁺ .

Example 28

2-[( E )-2-(2-Benzyloxy-3-methoxyphenyl)vinyl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1 H -benzene Imidazole

Intermediate 7 (500 mg, 1.404 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (914 mg, 2.808 mmol) and CuI (53 mg, 0.208 mmol) as described in Example 1. - chloro-5- (trifluoromethyl) pyridine the title compound was prepared conjugate (382mg, 2.106mmol) generates 507mg off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 3.87 (s, 3H), 4.98 (m, 2H), 6.89 (d, J = 7.5 Hz, 1H), 7.00-7.10 (m, 2H), 7.20-7.28 (m, 4H), 7.34-7.45 (m, 5H), 7.49 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 15.6 Hz, 1H), 8.79 (s, 1H); ESI-MS ( m/z ) 502.35 (M+H) ⁺ .

Example 29

1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl] -1 H -benzimidazole

Intermediate 6 (250 mg, 0.748 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (488 mg, 1.49 mmol) and CuI (29 mg, 0.149 mmol) as described in Example 1. Coupling of 3-dichloro-5-(trifluoromethyl)pyridine (243 mg, 1.122 mmol) afforded the title compound ield. Cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.81 (m, 8H), 3.84 (s, 3H), 4.82 (br s, 1H), 6.85-6.91 (m, 2H), 6.96- 7.06 (m, 3H), 7.28-7.35 (m, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.90-7.96 (m, 1H), 8.02 (d, J = 15.6 Hz, 1H), 8.23 - 8.18 (m, 1H), 8.91 (s, 1H); ESI-MS ( m/z ) 514.33 (M+H) ⁺ .

Example 30

6-(2-{( E )-2-[2-(cyclopentyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl)methyl nicotinate

Intermediate 6 (200 mg, 0.59 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (390 mg, 1.19 mmol) and CuI (23 mg, 0.11 mmol) as described in Example 1. - the title compound was prepared conjugate chloronicotinate (154mg, 0.89mmol), and generates an off-white solid product ^{50mg; IR (KBr) 2952,1575,1456,1263,1071,740 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.67-1.73 (m, 3H), 1.85-1.95 (m, 5H), 3.88 (s, 6H), 4.88-4.93 (m, 1H), 6.90 (d, J = 8.1 Hz, 1H) , 7.06 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.27-7.35 (m, 6H), 7.77 (d, J = 6.3 Hz, 1H), 8.10 (d, J =16.2 Hz, 1H); ESI-MS ( m/z ) 470.23 (M+H) ⁺ .

Example 31

2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1-(4-methylphenyl)-1 H -benzimidazole

Intermediate 5 (200 mg, 0.625 mmol) and 4-iodotoluene (205 mg, 0.937 mmol) and Cs in dry DMA (3 mL) as described in Example 1 in the presence of CuI (24 mg, 0.124 mmol) _{2 CO 3 (407mg, 1.252 mmol} ) of the title compound was prepared coupling of generating an off-white solid product ^{45mg; IR (Neat) 2926,1631,1515,1476,1267,985,742 cm -1} ; 1 H NMR (300 MHz, CDCl 3 δ 0.16-0.21 (m, 2H), 0.44-0.49 (m, 2H), 1.10 (br s, 1H), 2.46 (s, 3H), 3.75 (d, J = 5.4 Hz, 2H), 3.83 (s) , 3H), 6.83 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 6.0 Hz, 2H), 7.05 (d, J = 5.1 Hz, 2H), 7.13 (d, J = 6.6 Hz, 1H) ), 7.25-7.32 (m, 3H), 7.38 (d, J = 6.0 Hz, 2H), 7.85 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 12.0 Hz, 1H); APCI-MS ( m/z ) 411.37(M+H) ⁺ .

Example 32

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-(2-methoxyphenyl)-1 H -benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 2-iodoanisole (280 mg, 1.197 mmol) were obtained in dry DMA (5 ml) as described in Example 1 in dry DMA (5 mL). the title compound was prepared and coupling of _{Cs 2 CO 3 (390mg, 1.197mmol} ) , and generates an off-white solid product ^{31mg; IR (KBr) 3377,2952,1575,1474,1265,1072,747 cm -1} ; 1 H NMR (300 MHZ, CDCl ₃ ) δ 1.59-1.70 (m, 4H), 1.80-1.94 (m, 4H), 3.86 (s, 6H), 4.89 (br s, 1H), 6.85-6.91 (m, 1H), 7.00- 7.07 (m, 1H), 7.12-7.20 (m, 3H), 7.28-7.38 (m, 6H), 7.75 (s, 1H), 8.07 (d, J = 16.5 Hz, 1H); ESI-MS ( m/) z ) 441.20(M+H) ⁺ .

Example 33

4-{2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}benzonitrile

By intermediate 5 (200 mg, 0.625 mmol) in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (407 mg, 1.252 mmol) and CuI (24 mg, 0.124 mmol) as described in Example 1 4-iodo-benzonitrile (322mg, 1.562mmol) coupling title compound was prepared, 54mg generated off-white ^{solid; IR (KBr) 3412,2926,2233,1626,1508,1308,1267,1070,751 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.14-0.20 (m, 2H), 0.42-0.50 (m, 2H), 1.02 (br s, 1H), 3.69-3.77 (m, 2H), 3.83 (s, 3H) ), 6.90-6.96 (m, 1H), 7.00-7.07 (m, 1H), 7.15-7.21 (m, 2H), 7.35-7.42 (m, 3H), 7.45-7.52 (m, 2H), 7.65-7.73 (m, 2H), 7.95-8.08 (m, 1H), 8.75 (br s, 1H); APCI-MS ( m/z ) 422.19 (M+H) ⁺ .

Example 34

4-{2-[( E )-2-(2-benzyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}benzonitrile

Intermediate 7 (200 mg, 0.567 mmol) and 4 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (183 mg, 0.567 mmol) and CuI (21 mg, 0.118 mmol) as described in Example 1. - the title compound was prepared conjugate iodobenzonitrile (193mg, 0.841mmol) generates 37mg off-white ^{solid; IR (KBr) 2935,2229,1603,1450,1268,742 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 3.86(s,3H), 4.94(s,2H), 6.85-6.92(m,1H), 7.00-7.14(m,5H), 7.28-7.41(m,8H), 7.65(d, J = 7.5 Hz, 2H), 7.82 (d, J = 6.9 Hz, 1H), 8.02 (d, J = 15.6 Hz, 1H); ESI-MS ( m/z ) 458.10 (M+H) ⁺ .

Example 35

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-[4-(trifluoromethyl)phenyl]-1 H -benzimidazole

Intermediate 6 (100 mg, 0.299 mmol) and 1 in dry DMA (3 ml) in the presence of Cs ₂ CO ₃ (195 mg, 0.598 mmol) and CuI (11 mg, 0.059 mmol) as described in Example 1. Coupling of -iodo-4-(trifluoromethyl)benzene (122 mg, 0.449 mmol) afforded the title compound to afford 17 mg, m,j,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Cm ^-1 ; ¹ H NMR (300MHz, CDCl ₃ ) δ 1.47-1.56 (m, 4H), 1.65-1.72 (m, 4H), 3.83 (s, 3H), 4.83 (br s, 1H), 6.80-6.87 (m, 1H), 6.95-7.00 (m, 3H), 7.06-7.16 (m, 1H), 7.28-7.34 (m, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.80-7.87 (m , 3H), 8.08 (d, J = 16.2 Hz, 1H); APCI-MS ( m/z ) 479.33 (M+H) ⁺ .

Example 36

4-{2-[( E )-2-(2-butoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}benzonitrile

Intermediate 2 (200 mg, 0.625 mmol) was obtained in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (405 mg, 1.242 mmol) and CuI (24 mg, 0. preparation of 4-iodo-benzonitrile (214mg, 0.931mmol) coupling the compound to produce an off-white solid product ^{98mg; IR (KBr) 2925,2231,1602,1476,1385,1271,1074,747 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.92 (t, J = 6.9 Hz, 3H), 1.35-1.42 (m, 2H), 2.10-2.16 (m, 2H), 3.83 (s, 3H), 3.91 (d, J = 6.3 Hz, 2H), 6.80-6.86 (m, 1H), 7.00-7.07 (m, 3H), 7.11-7.18 (m, 1H), 7.30 (d, J = 6.9 Hz, 2H), 7.58 (d , J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 16.2 Hz, 1H); ESI-MS ( m /z ) 424.70 (M+H) ⁺ .

Example 37

2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1-[4-(trifluoromethyl)phenyl]-1 H -benzene Imidazole

Intermediate 5 (200 mg, 0.625 mmol) and 1 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.249 mmol) and CuI (24 mg, 0.124 mmol) as described in Example 1. - iodo-4- (trifluoromethyl) benzene (340mg, 1.249mmol) coupling title compound was prepared, 34mg generated off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 0.18 (br s, 2H), 0.42-0.49 (m, 2H), 1.05 (br s, 1H), 3.75 (d, J = 7.8 Hz, 2H), 3.83 (s, 3H), 6.82-6.90 (m, 1H), 7.00-7.09 (m , 2H), 7.14-7.20 (m, 3H), 7.30-7.36 (m, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.80-7.90 (m, 3H), 8.15 (d, J =16.5) Hz, 1H); APCI-MS ( m/z ) 465.39 (M+H) ⁺ .

Example 38

5-{2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-4-fluorobenzyl Nitrile

Intermediate 5 (200 mg, 0.625 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.252 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. - the title compound was prepared conjugate fluoro-5-iodo-benzonitrile (232mg, 0.937mmol) generates 102mg off-white ^{solid; IR (KBr) 2953,2229,1577,1490,1373,1266,1070,730 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.20 (d, J = 4.2 Hz, 2H), 0.50 (d, J = 4.2 Hz, 2H), 1.08 (br s, 1H), 3.70-3.77 (m, 2H) ), 3.83 (s, 3H), 6.84 (dd, J = 2.7, 6.6 Hz, 1H), 6.93 (d, J = 16.2 Hz, 1H), 6.99-7.05 (m, 3H), 7.20-7.30 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 15.6 Hz, 1H), 8.13 (s, 1H), 8.20 (s, 1H); ESI-MS ( m/z ) 440.53 (M+H) ⁺ .

Example 39

4-{2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-3-fluorobenzyl Nitrile

Intermediate 5 (200 mg, 0.681 mmol) and 3 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (442 mg, 1.362 mmol) and CuI (26 mg, 0.136 mmol) as described in Example 1. Preparation of the title compound by coupling of fluoro-4-iodobenzonitrile (201 mg, 0.816 mmol) afforded 36 mg of pale white solid product: ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.19-0.24 (m, 2H), 0.50-0.56 (m, 2H), 1.12 (br s, 1H), 3.69-3.79 (m, 2H), 3.82 (s, 3H), 6.78 (d, J = 15.9 Hz, 1H), 6.82-6.88 (m, 1H) , 6.96-7.06 (m, 2H), 7.18-7.28 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.52 (dd, J = 1.5, 8.1 Hz, 1H), 7.69 (s, 1H) ), 7.83 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 16.2 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H); ESI-MS ( m/z ) 440.48 (M+ H) ⁺ .

Example 40

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-(4-tert-butylbenzyl)-1 H -benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 4 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (389 mg, 1.196 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. Preparation of the title compound by coupling of tert-butylbenzyl bromide (203 mg, 0.898 mmol) afforded 37 mg of pale white solid product: IR (KBr) 2960, 1633, 1402, 1265, 1073, 737 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.31 (s, 9H), 1.45-1.53 (m, 2H), 1.61-1.81 (m, 6H), 3.83 (s, 3H), 4.81 (br s, 1H), 5.41 (s, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.99-7.09 (m, 3H), 7.19-7.29 (m, 7H), 7.77 (d, J = 8.4 Hz, 1H), 8.09 (d, J =1 5.6 Hz, 1H); ESI-MS ( m/z ) 481.53 (M+H) ⁺ .

Example 41

1-(2,4-difluorobenzyl)-2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole

Intermediate 5 (200 mg, 0.681 mmol) and 1 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (442 mg, 1.362 mmol) and CuI (26 mg, 0.136 mmol) as described in Example 1. - (bromomethyl) -2,4-difluorobenzene (244mg, 1.021mmol) coupling title compound was prepared, 36mg generated off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 0.18-0.24 (m, 2H), 0.48-0.54 (m, 2H), 1.21 (br s, 1H), 3.67-3.77 (m, 2H), 3.82 (s, 3H), 6.82 (s, 1H), 6.88-6.95 (m, 2H) ), 7.00-7.08 (m, 2H), 7.19-7.25 (m, 4H), 7.31 (t, J = 7.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.95-8.01 (m, 2H), 8.06 (s, 1H); ESI-MS ( m/z ) 447.53 (M+H) ⁺ .

Example 42

4-({2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}methyl)benzyl Nitrile

Intermediate 5 (100 mg, 0.341 mmol) and 4 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (221 mg, 0.682 mmol) and CuI (11 mg, 0.059 mmol) as described in Example 1. - the title compound was prepared conjugate (bromomethyl) benzonitrile (73mg, 0.372mmol), and generates an off-white solid product ^{56mg; 1 H NMR (300 MHz,} CDCl 3) δ 0.15-0.21 (m, 2H), 0.45-0.51 (m, 2H), 1, 12 (br s, 1H), 3.78 (d, J = 5.4 Hz, 2H), 3.85 (s, 3H), 5.53 (s, 2H), 6.87 (d, J = 6.3 Hz , 1H), 7.00-7.09 (m, 2H), 7.20-7.26 (m, 4H), 7.30-7.36 (m, 2H), 7.60 (d, J = 6.3 Hz, 2H), 7.83 (d, J = 6.3 Hz, 1H), 8.13 (d, J = 12.0 Hz, 1H); ESI-MS ( m/z ) 436, 26 (M+H) ⁺ .

Example 43

4-({2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}methyl)benzonitrile

Intermediate 6 (200 mg, 0.598 mmol) and 4-cyanobenzyl bromide in dry DMF (5 mL) as described in Example 1 in the presence of Cs ₂ CO ₃ (390 mg, 1.196 mmol) and Cu. (129mg, 0.658mmol) coupling title compound was prepared, 37mg generated off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 1.45-1.53 (m, 2H), 1.61-1.71 (m, 3H), 1.72- 1.81 (m, 5H), 3.86 (s, 3H), 4.81-4.89 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 7.07 (d) , J = 7.8 Hz, 1H), 7.14 (s, 1H), 7.16-7.26 (m, 4H), 7.31 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.83 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 15 Hz, 1H); ESI-MS ( m/z ) 450 (M+H) ⁺ .

Example 44

4-({2-[( E )-2-(2-{2-fluorobenzyloxy}-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}methyl Benzonitrile

Intermediate 8 (200 mg, 0.63 mmol) and 4-(bromomethyl)benzonitrile were obtained in dry DMF (5 mL) in the presence of Cs ₂ CO ₃ (410 mg, 1.26 mmol). (136mg, 0.704mmol) coupling title compound was prepared, 141mg generated off-white ^{solid; IR (KBr) 2945,2230,1581,1478,1275,1071,759 cm -1} ; 1 H NMR (300 MHz, CDCl 3) δ 3.85 (s, 3H), 5.11 (s, 2H), 5.37 (s, 2H), 6.89-6.94 (m, 1H), 6.96-7.02 (m, 1H), 7.04-7.10 (m, 6H), 7.12 -7.22 (m, 2H), 7.28-7.33 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 15.9 Hz, 1H); APCI-MS ( m/z ) 490.24 (M+H) ⁺ .

Example 45

2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)]-1-(2-thienyl)-1 H -benzimidazole

Intermediate 5 (200 mg, 0.625 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.251 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. - iodothiophene (197mg, 0.937mmol) coupling title compound was prepared, 59mg generated off-white ^{solid; IR (KBr) 3061,2924,1631,1577,1478,1270,977,735 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.20-0.30 (m, 2H), 0.40-0.50 (m, 2H), 1.58 (br s, 1H), 3.79 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H), 6.85 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 6.0 Hz, 1H), 7.07 (d, J = 5.7 Hz, 1H), 7.14-7.20 (m, 3H), 7.24-7.30 (m, 2H), 7.34-7.42 (m, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 8.15 (d, J = 12.3 Hz, 1H); APCI- MS ( m/z ) 403.25 (M+H) ⁺ .

Example 46

2-[( E )-2-(2-cyclopropoxy-3-methoxyphenyl)vinyl]-1-(1,3-thiazol-2-yl)-1 H -benzimidazole

Intermediate 5 (200 mg, 0.625 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.251 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. - the title compound was prepared conjugate bromothiazole (307mg, 1.875mmol), and generates an off-white solid product ^{84mg; IR (Neat) 2934,1626,1576,1476,1267,1087,740 cm -1} , 1 H NMR (300 MHz, CDCl ₃ ) δ 0.20-0.26 (m, 2H), 0.50-60 (m, 2H), 1.26 (br s, 1H), 3.78-.90 (m, 5H), 6.88 (d, J = 9.0 Hz, 1H) ), 7.02 (t, J = 6.0 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.33-7.47 (m, 2H), 7.52-7.60 (m, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 9.9 Hz, 1H), 8.25 (d, J = 12.6 Hz) , 1H); APCI-MS ( m/z ) 404.30 (M+H) ⁺ .

Example 47

2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-(1,3-thiazol-2-yl)-1 H -benzimidazole

Intermediate 6 (200 mg, 0.598 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (390 mg, 1.196 mmol) and CuI (23 mg, 0.119 mmol) as described in Example 1. Preparation of this compound by coupling of bromothiazole (147 mg, 0.898 mmol) afforded 43 mg of off white solid product: IR (KBr) 2957,1625,1499,1448,12658,1060,747 cm ^-1 ; ¹ H NMR (300 MHz , CDCl ₃ ) δ 1.52-1.58 (m, 2H), 1.62-1.69 (m, 2H), 1.76-1.90 (m, 4H), 3.85 (s, 3H), 4.89 (br s, 1H), 6.88 (d , J = 7.2 Hz, 1H), 7.00-7.06 (m, 1H), 7.15 (d, J = 6.9 Hz, 1H), 7.28-7.38 (m, 2H), 7.45 (s, 1H), 7.49 (d, J =12.0 Hz, 1H), 7.61 (d, J = 5.7 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 8.18 (d, J = 12.0 Hz, 1H) ESI-MS ( m/z ) 418.53 (M+H) ⁺ .

Example 48

2-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-1,3- Thiazol-5-nitrile

Intermediate 6 (200 mg, 0.59 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (390 mg, 1.19 mmol) and CuI (22 mg, 0.111 mmol) as described in Example 1. Coupling of the bromo-1,3-thiazole-5-carbonitrile (135.8 mg, 0.71 mmol) afforded the title compound to give the desired product, m, m,j,j,j,j,j,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.69 (m, 4H), 1.74-1.83 (m, 4H), 3.88 (s, 3H), 4.92 (br s, 1H), 6.93 (d , J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.36-7.45 (m, 2H), 7.60 (d, J = 15.9 Hz) , 1H), 7.85 (d, J = 6.9 Hz, 2H), 8.23 (s, 1H), 8.30 (s, 1H); ESI-MS ( m/z ) 443.16 (M+H) ⁺ .

Example 49

2-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-4-methyl-1 , 3-thiazole-5-carbonitrile

Intermediate 6 (200 mg, 0.589 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (390 mg, 1.189 mmol) and CuI (23 mg, 0.118 mmol) as described in Example 1. Coupling of -iodo-4-methyl-1,3-thiazole-5-carbonitrile (180 mg, 0.714 mmol) afforded the title compound 758 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.57-1.68 (m, 4H), 1.76-1.86 (m, 4H), 2.73 (s, 3H), 3.86 (s, 3H), 4.90 ( Br s,1H), 6.90 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 6.6 Hz) , 2H), 7.54 (d, J = 16.2 Hz, 1H), 7.77-7.83 (m, 2H), 8.20 (d, J = 15.6 Hz, 1H); ESI-MS ( m/z ) 457.54 (M+H ) ⁺ .

Example 50

2-{2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-1,3- Benzothiazole

Intermediate 5 (200 mg, 0.625 mmol) and 2 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (407 mg, 1.251 mmol) and CuI (24 mg, 0.125 mmol) as described in Example 1. - the title compound was prepared conjugate-chloro-1,3-benzothiazole (171mg, 1.251mmol), and generates an off-white solid product ^{55mg; IR (KBr) 2936,1668,1514,1358,1271,1069,736 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.18-0.24 (m, 2H), 0.40-0.48 (m, 2H), 1.18 (br s, 1H), 3.81 (s, 2H), 3.84 (s, 3H) , 6.86 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.30-7.37 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 6.9 Hz, 1H), 7.74 (d, J = 16.2 Hz, 1H), 7.84 (t, J = 8.4 Hz, 2H), 7.92 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.34 (d, J = 16.2 Hz, 1H); APCI-MS ( m/z ) 454.30 (M+H) ⁺ .

Example 51

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-methoxy-1 H -benzimidazol-1-yl} Nitrile

Intermediate 15 (200 mg, 0.549 mmol) and 6 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (358 mg, 1.098 mmol) and CuI (21 mg, 0.109 mmol) as described in Example 1. Coupling of chloronicotinonitrile (114 mg, 0.824 mmol) gave the title compound. The compound was further recrystallized from ethyl acetate to give the desired 80mg, as an off-white solid ^{regioisomers; IR (KBr) 2957,2232,1590,1477,1267,1158,969 cm -1} ; 1 H NMR (300 MHZ, CDCl ₃ ) δ 1.60-1.77 (m, 8H), 3.86 (s, 3H), 3.90 (s, 3H), 4.88 (br s, 1H), 6.88-6.99 (m, 1H), 6.99 -7.12 (m, 2H), 7.33 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H) , 8.07 (d, J = 16.2 Hz, 1H), 8.16-8.22 (m, 2H), 9.02 (d, J = 4.2 Hz, 1H); APCt-MS ( m/z ) 467.91 (M+H) ⁺ .

Example 52

6-(6-Chloro-2-{( E )-2-[3-methoxy-2-(2-methylpropoxy)phenyl]vinyl}-1 H -benzimidazole-1- Pyridine-3-carbonitrile

Intermediate 32 (150 mg, 0.315 mmol) was dissolved in EtOAc (EtOAc) After the reaction was completed, excess acetic acid was evaporated, and the mixture was diluted with water and ethyl acetate (2×25ml). Then the combined organic layer was washed with water (3 × 20ml), brine (20ml) and dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography using 12% acetone in petroleum ether to yield 70 mg of product: IR (KBr) 2950, 2231, 1590, 1479, 1270, 1004, 785 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.97 (d, J = 6.3 Hz, 6H), 1.90-1.97 (m, 1H), 3.69 (d, J = 6.3 Hz, 2H), 3.81 (s, 2H), 7.06 ( Br s, 2H), 7.25 (d, J = 16.2 Hz, 2H), 7.37 (d, J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 16.2 Hz, 2H), 8.69 (d, J = 6.9 Hz, 1H), 9.25 (s, 1H); ESI-MS ( m/z ) 459.31 (M+H) ⁺ .

Example 53

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-fluoro-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 13 (300 mg, 0.852 mmol) and 6 in dry DMA (5 ml) in the presence of Cs ₂ CO ₃ (555 mg, 1.704 mmol) and CuI (33 mg, 0.107 mmol) as described in Example 1. Coupling of chloronicotinonitrile (177 mg, 1.278 mmol) to prepare a mixture of compounds. The compound was further recrystallized from ethyl acetate, to give 70mg of the desired regioisomer as an off-white ^{solid; IR (KBr) 2959,2232,1592,1477,1267,1173,800 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.61-1.78 (m, 8H), 3.85 (s, 3H), 4.87 (br s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.97-7.11 ( m, 3H), 7.20-7.28 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 6.6 Hz, 1H), 7.70-7.76 (m, 1H), 8.11 (d) , J = 15.0 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 8.99 (s, 1H); APCI-MS ( m/z ) 455.35 (M+H) ⁺ .

Example 54

6-{6-Chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Intermediate 14 (1 g, 2.711 mmol) was obtained in dry DMA (15 mL) in the presence of Cs ₂ CO ₃ (1.76 g, 5.40 mmol) and CuI (103 mg, 0.540 mmol) as described in Example 1 Coupling of 6-chloronicotinonitrile (488 mg, 3.522 mmol) afforded the title compound to give a crude product of 600 mg, which is a mixture of regioisomers. The isomers were separated by preparative HPLC to yield 100 mg of the crude product as a pale white solid (6-chloro isomer); IR (KBr) 2953, 2236, 1591, 1479, 1268, 1067, 769 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.55-1.65 (m, 4H), 1.68-1.76 (m, 4H), 3.81 (s, 3H), 4.87 (br s, 1H), 7.06 (s, 2H), 7.20-7.28 (m, 2H), 7.37 (d, J = 9.3, 1H), 7.62 (s, 1H), 7.77 (d, J = 8.4, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 16.2, 1H), 8.69 (d, J = 7.5, 1H), 9.25 (s, 1H); ESI-MS ( m/z ) 471.25 (M) ⁺ .

Example 55

6-{5-Chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

The product of the greater polarity (68 mg) was obtained from mp EtOAc (m.) , 1477,1268,1068,776 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.59-1.67 (m, 4H), 1.69-1.77 (m, 4H), 3.81 (s, 3H), 4.87(br s,1H),7.06(s,2H),7.22-7.34(m,3H),7.56(d, J =8.4,1H),7.83(s,1H),7.99(d, J =8.4, 1H), 8.16 (d, J = 16.2 Hz, 1H), 8.70 (d, J = 7.8, 1H), 9.25 (s, 1H); ESI-MS ( m/z ) 471.21. (M+H) ⁺ .

Example 56

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)ethenyl]-5-methoxy-1 H -benzimidazol-1-yl } Nicotinonitrile

As described in Example 52, in glacial acetic acid The title compound was prepared by cyclization of Intermediate 34, 120mg generating off-white ^{solid; IR (KBr) 3429,2959,2233,1590,1477,1267,1159 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.69-1.77 (m, 8H), 3.86 (s, 3H), 3.90 (s, 3H), 4.89 (br s, 1H), 6.88-6.96 (m, 3H) , 7.03 (t, J = 7.8 Hz, 1H), 7.29-7.34 (m, 2H), 7.44 (d, J = 9.3 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 6.9 Hz, 2H), 9.01 (s, 1H); ESI-MS ( m/z ) 467.25 (M+H) ⁺ .

Example 57

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-5-(trifluoromethyl)-1 H -benzimidazole- 1-based nicotinonitrile

As described in Example 52, in glacial acetic acid The title compound was prepared by cyclization of intermediate 33 generates 268mg off-white ^{solid; IR (KBr) 2954,2233,1590,1480,1267,1119,771 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61-I.68 (m, 4H), 1.70-1.80 (m, 4H), 3.87 (s, 3H), 4.91 (br s, 1H), 6.91 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H) , 7.60-7.66 (m, 2H), 8.11 (s, 1H), 8.23-8.29 (m, 2H), 9.02 (s, 1H); ESI-MS ( m/z ) 505.17 (M+H) ⁺ .

Example 58

6-{6-(Difluoromethoxy)-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazole -1-yl}nicotinonitrile

As described in Example 1, _{Cs 2 CO 3 (326mg, 1.0mmol} ) and CuI (19.5mg, 0.10mmol) in the presence of, in dry DMA (3ml) by condensation of Intermediate 16 (200mg, 0.50mmol) and Coupling of 6-chloronicotinonitrile (104 mg, 0.75 mmol) gave the crude title compound. This product was further recrystallized from ethyl acetate to give EtOAc (yield: EtOAc: EtOAc ^{: 1} ; APCI-MS ( m/z ) 503.18 (M+H) ⁺ .

Example 59

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)ethenyl]-5-(difluoromethoxy)-1 H -benzimidazole -1-yl}nicotinonitrile

As described in Example 52, in glacial acetic acid The title compound was prepared by cyclization of intermediate 35 generates 268mg off-white ^{solid; IR (KBr) 2966,2235,1595,1478,1267,1124,784 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.69 (m, 4H), 1.72-1.80 (m, 4H), 3.87 (s, 3H), 4.90 (br s, 1H), 6.56 (t, J = 73.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.59-7.66 (m, 3H), 8.19-8.24 (m, 2H), 9.02 (s, 1H); ESI-MS ( m/z ) 503.16 (M+H) ⁺ .

Example 60

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-fluoro-1 H -benzimidazol-1-yl}nicotinic acid A ester

Intermediate 13 (200 mg, 0.568 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (370 mg, 1.136 mmol) and CuI (22 mg, 0.113 mmol) as described in Example 1. Coupling of a compound of -chloronicotinate (117 mg, 0.681 mmol) to prepare a compound. This compound was further recrystallized from ethyl acetate, to give 75mg of the desired regioisomer as an off-white ^{solid; IR (KBr) 2951,1632,1575,1475,1265,1071,772 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.56-1.66 (m, 4H), 1.78-1.85 (m, 4H), 3.81 (s, 3H), 3.89 (d, J = 7.8 Hz, 3H), 4.85 (br) s,1H), 6.98-7.11(m,4H),7.33-7.44(m,3H), 7.50-7.60(m,3H),8.02-8.11(m,1H);ESI-MS( m/z ) 488.83 (M+H) ⁺ .

Example 61

2-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Nicotinonitrile

Intermediate 23 (200 mg, 0.54 mmol) and 2 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (352 mg, 1.081 mmol) and CuI (21 mg, 0.108 mmol) as described in Example 1. Coupling of chloronicotinonitrile (113 mg, 0.810 mmol) gave the title compound. The crude product was purified by silica gel column chromatography using 12% acetone in petroleum ether to afford 111 mg of pale white solid product: IR (KBr) 2960, 2233, 1624, 1467, 1437, 1261, 1072, 778 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.68 (m, 4H), 1.72-1.80 (m, 4H), 3.84 (s, 3H), 4.81 (br s, 1H), 6.87 (d, J = 7.2 Hz , 1H), 6.93-7.05 (m, 4H), 7.60-7.65 (m, 2H), 7.97 (d, J = 16.2 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.95 (s, 1H); APCI-MS ( m/z ) 473.24 (M+H) ⁺ .

Example 62

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-5,6-dimethyl-1 H -benzimidazole-1 -based nicotinonitrile

Intermediate 25 (200 mg, 0.552 mmol) and 6 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (360 mg, 1.104 mmol) and CuI (21 mg, 0.110 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (116mg, 0.828mmol) generates 92mg off-white ^{solid; IR (KBr) 2960,2230,1593,1476,1269,1069,979 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.64-1.82 (m, 8H), 2.32 (d, J = 9.3 Hz, 6H), 3.81 (s, 3H), 4.86 (br s, 1H), 7.02 (s, 2H), 7.24 ( d, J = 15.6 Hz, 2H), 7.36 (s, 1H), 7.53 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 16.2 Hz, 1H), 8.66 ( d, J = 8.4 Hz, 1H), 9.23 (s, 1H); APCI-MS ( m/z ) 465.28 (M+H) ⁺ .

Example 63

6-{2-[( E )-2-(2-ethoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Nitrile

Intermediate 17 (250 mg, 0.62 mmol) and 6 in dry DMF (6 mL) in the presence of Cs ₂ CO ₃ (303 mg, 0.93 mmol) and CuI (11 mg, 0.062 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (128mg, 0.93mmol), and generates an off-white solid product ^{90mg; IR (KBr) 2973,2231,1593,1470,1269,1156,778 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.33 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.04-4.11 (m, 2H), 6.93 (s, 1H), 7.02-7.08 (m, 2H), 7.28 (s, 1H), 7.43-7.49 (m, 1H), 7.58-7.63 (m, 2H), 8.14 (d, J = 16.2 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H), 9.02 ( s, 1H); APCI-MS ( m/z ) 433.25 (M+H) ⁺ .

Example 64

6-{2-[( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}- Nicotinonitrile

Intermediate 18 (200 mg, 0.558 mmol) and 6 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (355 mg, 1.17 mmol) and CuI (22 mg, 0.111 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (116mg, 0.837mmol) generates 110mg off-white ^{solid; IR (KBr) 2961,2233,1592,1470,1270,1157,781 cm 1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.932 (t, J = 7.2 Hz, 3H), 1.39-1.46 (m, 2H), 1.62-1.68 (m, 2H), 3.87 (s, 3H), 3.97 (t, J = 6.3 Hz, 2H), 6.91 (t, J = 6.9 Hz, 1H), 7.02-7.07 (m, 2H), 7.23-7.28 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 8.13 (d, J = 16.2 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 9.02 (s, 1H); ESI-MS ( m/z ) 461.40 (M+ H) ⁺ .

Example 65

6-{5,6-Difluoro-2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nitrile

By intermediate 19 (200 mg, 0.537 mmol) in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (350.2 mg, 1.074 mmol) and CuI (21 mg, 0.107 mmol) as described in Example 1 the title compound was prepared coupling of 6-chloro-nicotinonitrile (112mg, 0.806mmol) generates 93mg off-white ^{solid; IR (KBr) 2956,2236,1593,1471,1270,1159,782 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 0.88-0.9 (m, 3H), 1.32-1.39 (m, 4H), 1.62 (d, J = 6.3 Hz, 2H), 3.81 (s, 3H), 3.91 (br s, 2H), 7.05 (s, 2H), 7.24-7.29 (m, 2H), 7.65-7.71 (m, 1H), 7.80-7.86 (m, 1H), 7.99 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 15.9 Hz, 1H), 8.70 (d, J = 6.3 Hz, 1H), 9.24 (s, 1H); APCI-MS ( m/z ) 475.22 (M+H) ⁺ .

Example 66

6-{5,6-Difluoro-2-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nicotinonitrile

Intermediate 20 (200 mg, 0.55 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (364 mg, 1.1 mmol) and CuI (22 mg, 0.11 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (116mg, 0.83mmol), the product was 83mg of an off-white ^{solid; IR (KBr) 2958,2234,1593,1470,1270,1158,779 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.97 (d, J = 6.3 Hz, 6H), 1.98-2.06 (m, 1H), 3.73 (d, J = 6.9 Hz, 2H), 3.86 (s, 3H), 6.91 (d, J = 6.3 Hz, 1H), 7.01-7.10 (m, 2H), 7.36 (s, 1H), 7.43-7.49 (m, 1H), 7.56-7.61 (m, 2H), 8.15 (d, J = 16.3 Hz , 1H), 8.19-8.24 (m, 1H), 9.01 (s, 1H); ESI-MS ( m/z ) 461.25 (M+H) ⁺ .

Example 67

6-{2-[( E )-2-(2-cyclobutylmethoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl smoke Nitrile

As described in Example 1, in the presence of _{Cs 2 CO 3 (352.5mg, 1.0mmol} ) and CuI (20.6mg, 0.10mmol), in dry DMF (5ml) via the intermediate 22 (200mg, 0.54mmol) and 6-chloro-nicotinonitrile (112mg, 0.81mmol) coupling title compound was prepared, 109mg generated off-white ^{solid; IR (KBr) 2937,2233,1592,1471,1395,1269,1158,782 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.76-1.86 (m, 4H), 1.95-2.04 (m, 2H), 2.65-2.72 (m, 1H), 3.87 (s, 3H), 3.97 (d, J = 6.9 Hz, 2H), 6.90 (t, J = 6.3 Hz, 1H), 7.01-7.09 (m, 2H), 7.20 (s, 1H), 7.44-7.49 (m, 1H), 7.56-7.61 (m, 2H) , 8.14 (d, J = 15.6 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 9.02 (s, 1H); APCI-MS ( m/z ) 473.27 (M+H) ⁺ .

Example 68

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Nicotinonitrile

Intermediate 23 (200 mg, 0.541 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (351 mg, 1.081 mmol) and CuI (20 mg, 0.108 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (112mg, 0.811mmol), and generates an off-white solid product ^{97mg; 1 H NMR (300 MHZ,} CDCl 3) δ 1.65-1.81 (m, 8H), 3.85 (s, 3H), 4.88(br s,1H), 6.87 (dd, J = 1.5, 7.8 Hz, 1H), 6.97-7.07 (m, 2H), 7.17 (d, J = 15, 9 Hz, 1H), 7.39-7.45 (m , 1H), 7.54-7.60 (m, 2H), 8.11 (d, J = 15.9 Hz, 1H), 8.20 (dd, J = 2.7, 9.0 Hz, 1H), 8.99 (d, J = 1.5 Hz, 1H) ; ESI-MS ( m/z ) 473.53 (M+H) ⁺ .

Example 69

6-{5,6-Difluoro-2-[( E )-2-(2-hydroxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile

Add boron tribromide (BBr ₃ ) to a solution of Example 68 (500 mg, 1.059 mmol) in dry DCM (20 mL) and cooled to -70 ° C under a nitrogen atmosphere, and the reaction mixture was at -70 Stir at °C for 30 min. After the reaction was completed, the reaction mixture was neutralized with a saturated NaHCO ₃ solution, and the precipitated solid was filtered. The obtained crude product was purified by silica gel column chromatography using 3% methanol in chloroform to yield 35 mg of product: IR (KBr) 2922, 2239, 1592, 1472, 1266, 1125, 769 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.81 (s, 3H), 6.77 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 7.17-7.27 (m, 2H), 7.67 ( d, J = 7.2 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 15.6 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 9.25 (d, J = 15.9 Hz, 1H); APCI-MS ( m/z ) 405.37 (M+H) ⁺ .

Example 70

6-{6-Chloro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-5-fluoro-1 H -benzimidazole-1 -based nicotinonitrile

As described in Example 52, in glacial acetic acid The title compound was prepared by cyclization of Intermediate 36, 115mg generating off-white ^{solid; IR (KBr) 2953,2234,1592,1459,1266,1149,757 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60-1.69 (m, 4H), 1.71-1.78 (m, 4H), 3.87 (s, 3H), 4.90 (br s, 1H), 6.91 (d, J = 7.2 Hz, 1H), 7.00-7.10 (m, 2H), 7.20 (d, J = 15.6 Hz, 1H), 7.56-7.65 (m, 3H), 8.20 (d, J = 16.2 Hz, 2H), 9.03 ( s, 1H); ESI-MS ( m/z ) 489.15 (M+H) ⁺ .

Example 71

6-{5-Chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-(trifluoromethyl)-1 H -benzo Imidazol-1-yl}nicotinonitrile

Intermediate 26 (200 mg, 0.45 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (299 mg, 0.91 mmol) and CuI (18 mg, 0.09 mmol) as described in Example 1. - the title compound was prepared conjugate chloronicotinonitrile (96mg, 0.68mmol) and 45mg generating off-white ^{solid; IR (KBr) 2963,2232,1591,1478,1269,1132,1072,775 cm -1} ; 1 H NMR ( 300 MHz, CDCl ₃ ) δ 1.60-1.70 (m, 4H), 1.75-1.82 (m, 4H), 3.87 (s, 3H), 4.92 (br s, 1H), 6.90-9.96 (m, 1H), 7.03 -7.10 (m, 1H), 7.16-7.26 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.90-7.98 (m, 1H), 8.17 (s, 1H) ), 8.23-8.30 (m, 2H), 9.06 (s, 1H); APCI-MS ( m/z ) 539.17 (M+H) ⁺ .

Example 72

6-{5,6-Dichloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nicotinonitrile

Intermediate 24 (200 mg, 0.497 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (354 mg, 0.99 mmol) and CuI (20 mg, 0.099 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (103mg, 0.746mmol), and generates an off-white solid product ^{30mg; IR (KBr) 2951,2234,1590,1442,1270,1070,776 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.66-1.79 (m, 8H), 3.87 (s, 3H), 4.91 (br s, 1H), 6.91 (d, J = 7.2 Hz, 1H), 7.00-7.10 (m, 2H), 7.17-7.26(m,1H), 7.61(d, J =8.4 Hz,1H), 7.71(s,1H),7.91(s,1H),8.18-8.26(m,2H),9.04(s,1H) ; ESI-MS ( m/z ) 505.14 (M+H) ⁺ .

Example 73

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Pyridazine-3-carboxylic acid ethyl ester

Pass intermediate 23 (2.0 g, 5.13 mmol) in dry DMA (20 mL) in the presence of Cs ₂ CO ₃ (3.4 g, 10.36 mmol) and CuI (0.20 g, 1.023 mmol) as described in Example 1. The title compound was prepared by coupling with 6-chloropyridazine-3-carboxylic acid ethyl ester (1.5 g, 7.499 mmol) to afford 710 mg (yield: s, s, s, s, s, s, s, s, s, 1155, 773 cm ^-1 ; ¹ H NMR (300 MHZ, CDCl ₃ ) δ 1.58-1.66 (m, 8H), 1.68-1.79 (m, 3H), 3.86 (s, 3H), 4.59-4.66 (m, 2H) ), 4.88 (br s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.08-7.18 (m, 2H), 7.52-7.65 (m, 2H) ), 7.80 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 16.2 Hz, 1H), 8.45 (d, J = 8.7 Hz, 1H); ESI-MS ( m/z ) 521.23 (M+ H) ⁺ .

Example 74

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Pyridazine-3-carboxylic acid

The title compound was prepared by mp EtOAc (EtOAc: EtOAc (EtOAc) 2954, 2233, 1623, 1575, 1477, 1267, 1145, 775 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.65-1.75 (m, 8H), 3.81 (s, 3H), 4.87 ( Br s,1H),7.05(s,2H),7.15(s,1H), 7.20(s,1H), 7.67(t, J =7.8 Hz,1H),7.89(t, J =7.8 Hz,1H) , 8.14 (d, J = 16.2 Hz, 1H), 8.26 (d, J = 9.0, 1H), 8.53 (d, J = 8.7, 1H); ESI-MS ( m/z ) 492.22 (M) ⁺ .

Example 75

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Pyridazin-3-indolamine

The title compound was prepared from EtOAc (EtOAc: EtOAc: EtOAc: 738 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.64-1.74 (m, 8H), 3.81 (s, 3H), 4.87 (br s, 1H), 7.05 (br s, 2H), 7.16-7.26(m,2H), 7.66(t, J = 7.2 Hz, 1H), 7.90 (t, J = 7.5 Hz, 1H), 8.14 (d, J = 15.6 Hz, 2H), 8.32 (d, J = 8.7, 1H), 8.52 (d, J = 8.7, 1H), 8.83 (s, 1H); ESI-MS ( m/z ) 491.22 (M) ⁺ .

Example 76

6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethenyl]-5,6-difluoro-1 H -benzimidazol-1-yl} Pyridazine-3-carbonitrile

Example 75 (200 mg, 0.40 mmol) was dehydrated by using trifluoroacetic anhydride (128.5 mg, 0.610 mmol) in the presence of triethylamine (124 mg, 1.22 mmol). The title compound, off-white solid product 79mg ^{generated; IR (KBr) 2957,1623,1574,1474,1269,757 cm -1} ; 1 H NMR (300 MHz, DMSO- d 6) δ 1.62-1.79 (m, 8H) , 3.81 (s, 3H), 4.88 (br s, 1H), 7.06 (s, 2H), 7.15 (d, J = 16.2 Hz, 1H), 7.27 (s, 1H), 7.65-7.71 (m, 1H) , 7.88-7.94 (m, 1H), 8.17 (d, J = 16.2 Hz, 1H), 8.47 (d, J = 9.3, 1H), 8.78 (d, J = 8.7, 1H); APCI-MS ( m/ z ) 474.17(M+H) ⁺ .

Example 77

6-{2-[( E )-2-(2-(1-ethylpropoxy)-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazole -1-yl}nicotinonitrile

As described in Example 1, in the presence of _{Cs 2 CO 3 (525mg, 1.612mmol} ) and CuI (30.8mg, 0.161mmol), in dry DMA (5ml) via the intermediate 21 (301 mg, 0.809mmol) and 6-chloro-nicotinonitrile (168mg, 1.209mmol) coupling title compound was prepared, 169mg generated off-white ^{solid; IR (KBr) 2965,2235,1593,1471,1268,1073,771 cm -1} ; 1 H NMR ( 300 MHz, CDCl ₃ ) δ 1.58-1.67 (m, 10H), 3.86 (s, 3H), 4.23 (t, J = 6.0 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.01 (t , J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.17-7.25 (m, 1H), 7.42-7.47 (m, 1H), 7.55-7.61 (m, 2H), 8.14 ( s, 1H), 8.17-8.23 (m , 1H), 9.02 (s, 1H); ESI-MS (m / z) 475.21 (m) +.

Example 78

6-{5,7-Difluoro-2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nitrile

The title compound was prepared by cyclization of intermediate 37 in glacial acetic acid as described in Example 52 to yield 33 mg of off white solid product: IR (KBr) 3020, 2935, 2238, 1600, 1477, 1217, 1125, 771 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.85-0.95 (m, 3H), 1.30-1.40 (m, 4H), 1.69-1.74 (m, 2H), 3.86 (s, 3H), 3.95 ( t, J = 6.9 Hz, 2H), 6.81 (t, J = 10.2 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 7.00-7.06 (m, 2H), 7.19 (d, J = =15.9) Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.57-7.62 (m, 1H), 8.18 (m, 2H), 8.97 (s, 1H); APCI-MS ( m/z ) 475.42 ( M+H) ⁺ .

Example 79

6-{5,7-Difluoro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazole-1- Nicotinic nitrile

The title compound was prepared by cyclization of intermediate 38 in glacial acetic acid to give 39 mg of pale white solid product as of <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&^-1; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-1.78 (m, 8H), 3.86 (s, 3H), 4.88 (br s, 1H), 6.80 (t, J = 9.3 Hz, 1H), 6.89 (d, J = 6.9 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (d, J = 15.9 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.56-7.62 (m) , 1H), 8.17-8.22 (m, 2H), 8.97 (s, 1H); APCI-MS ( m/z ) 473.42 (M+H) ⁺ .

Example 80

6-{4,6-Difluoro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazole-1- Nicotinic nitrile

Intermediate 27 (200 mg, 0.540 mmol) and 6 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (352 mg, 1.081 mmol) and CuI (22 mg, 0.108 mmol) as described in Example 1. This compound was prepared by coupling of chloronicotinonitrile (113 mg, 0.810 mmol) to give a crude product. This product was further recrystallized from ethyl acetate to give the desired 91mg, as an off-white solid ^{regioisomers; IR (KBr) 2956,2232,1592,1429,1225,1069,772 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 1.60-1.75 (m, 8H), 3.81 (s, 3H), 4.88 (br s, 1H), 7.06 (s, 2H), 7.24-7.30 (m, 4H) ), 8.00 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 15.9 Hz, 1H), 8.71 (d, J = 7.8 Hz, 1H), 9.25 (s, 1H); APCI-MS ( m /z ) 473.17(M+H) ⁺ .

Example 81

6-{2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-4,5,6-trifluoro-1 H -benzimidazol-1-yl } Nicotinonitrile

As described in Example 1, in the presence of _{Cs 2 CO 3 (350.2mg, 1.074mmol} ) , and CuI (21mg, 0.107mmol), in dry DMA (5ml) via the intermediate 28 (200 mg, 0.537mmol) Coupling with 6-chloronicotinonitrile (112 mg, 0.806 mmol) gave the title compound. This product was further recrystallized from ethyl acetate to give the desired 93mg, as an off-white solid ^{regioisomers; IR (KBr) 2935,2236,1578,1480,1271,1074,778 cm -1} ; 1 H NMR (300 MHz, DMSO- d 6) δ 0.910 (t, J = 6.0 Hz, 3H), 1.32-1.39 (m, 4H), 1.62 (br s, 2H), 3.81 (s, 3H), 3.92 ( Br s,2H),7.06(s,1H),7.21(s,2H),7.57(br s,1H),8.00(d, J =6.0 Hz,1H),8.17(d, J =15.0 Hz,1H ), 8.72 (d, J = 6.0 Hz, 1H), 9.25 (br s, 1H); ESI-MS ( m/z ) 493.27 (M+H) ⁺ .

Example 82

6-(2-{( E )-2-[3-(Difluoromethoxy)-2-pentyloxyphenyl]vinyl}-5,6-difluoro-1 H -benzimidazole-1 -based nicotinonitrile

As described in Example 1, _{Cs 2 CO 3 (239.5mg, 0.73mmol} ) , and CuI (14mg, 0.073mmol) in the presence of, in dry DMA (3ml) by condensation of Intermediate 29 (150mg, 0.36mmol) and 6-chloro-nicotinonitrile (66.2mg, 0.47mmol) coupling title compound was prepared, 53mg generated off-white ^{solid; IR (KBr) 2933,2233,1592,1473,1267,1122,795 cm -1} ; 1 H NMR ( 300 MHz, CDCl ₃ ) δ 0.93 (br s, 3H), 1.39 (br s, 4H), 1.73 (br s, 2H), 4.00 (br s, 2H), 6.55 (d, J = 74.7 Hz, 1H) , 7.10 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.36 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 8.15 (d, J = 15.6 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 9.03 (s, 1H); ESI -MS( m/z ) 511.15(M+H) ⁺ .

Example 83

6-(2-{( E )-2-[2-(cyclobutylmethoxy)-3-difluoromethoxyphenyl]ethenyl}-5,6-difluoro-1 H -benzimidazole- 1-based nicotinonitrile

Intermediate 30 (200 mg, 0.558 mmol) and 6 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (355 mg, 1.117 mmol) and CuI (22 mg, 0.111 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (116mg, 0.837mmol) generates 110mg off-white ^{solid; IR (KBr) 2929,2238,1471,1269,1124,758 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.80-1.92 (m, 4H), 2.04 (br s, 2H), 3.99 (d, J = 6.3 Hz, 2H), 6.55 (t, J = 74.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.14-7.21 (m, 2H), 7.36 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.61 (br s, 2H), 8.14 (d) , J =16.2 Hz, 1H), 8.25 (d, J = 7.8 Hz, 2H), 9.03 (s, 1H); ESI-MS ( m/z ) 509.08 (M+H) ⁺ .

Example 84

6-(2-{( E )-2-[2-(cyclopentyloxy)-3-difluoromethoxyphenyl]ethenyl}-5,6-difluoro-1 H -benzimidazole- 1-based nicotinonitrile

Intermediate 31 (200 mg, 0.492 mmol) and 6 in dry DMA (5 mL) in the presence of Cs ₂ CO ₃ (320 mg, 0.98 mmol) and CuI (18 mg, 0.098 mmol) as described in Example 1. - coupling chloronicotinonitrile title compound was prepared (102mg, 0.738mmol) generates 119mg off-white ^{solid; IR (KBr) 2961,2236,1590,1462,1121,1036,770 cm -1} ; 1 H NMR (300 MHz , CDCl ₃ ) δ 1.59-1.66 (m, 4H), 1.70-1.82 (m, 4H), 4.84 (br s, 1H), 6.53 (t, J = 74.7 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 12.6 Hz, 1H), 7.35-7.45 (m, 2H), 7.61 (br s, 2H), 8.16 (d, J =15.9 Hz, 1H), 8.26 (br s, 1H), 9.03 (s, 1H); ESI-MS ( m/z ) 509.14 (M+H) ⁺ .

Example 85

2-[( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzimidazole

Intermediate 2 (200 mg, 0.625 mmol) and 2 in dry DMA (3 mL) in the presence of Cs ₂ CO ₃ (405 mg, 1.242 mmol) and CuI (24 mg, 0.124 mmol) as described in Example 1. - chloro-5- (trifluoromethyl) pyridine the title compound was prepared conjugate (169mg, 0.931mmol) generates 45mg off-white ^{solid; IR (KBr) 2964,1579,1375,1267,1137,717 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.90 (t, J = 7.2 Hz, 3H), 1.34-1.44 (m, 2H), 1.60-1.68 (m, 2H), 3.84 (s, 3H), 3.94 ( t, J = 6.3 Hz, 2H), 6.86 (d, J = 7.5 Hz, 1H), 6.99-7.09 (m, 2H), 7.27-7.39 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H) ), 7.61 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 15.3 Hz, 1H), 8.18 (s, 1H), 8.99 (s, 1H) ESI-MS ( m/z ) 468.31 (M+H) ⁺ .

Example 86

6-{2-[( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl} Nitrile

As described in Example 52, in glacial acetic acid manipulation by cyclization of intermediate 40 to prepare the title compound, 219mg generating an off-white solid ^{product; IR (KBr) 2952,2233,1578,1479,1271,1048 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 0.88-0.95 (m, 3H), 1.39-1.46 (m, 2H), 1.59-1.68 (m, 2H), 3.82 (s, 3H), 3.91-3.98 ( m, 2H), 7.08 (s, 2H), 7.29 (br s, 1H), 7.42-7.55 (m, 2H), 8.18-8.27 (m, 3H), 8.36 (br s, 1H), 8.60-8.73 ( m, 1H), 9.22 (s, 1H); APCI-MS ( m/z ) 426.30 (M+H) ⁺ .

Example 87

6-{2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl} Nitrile

As described in Example 52, the title compound was prepared by cyclization of intermediate 41 in glacial acetic acid manipulation, generating off-white solid 131mg; IR (KBr) 2930,2232,1592,1479,1368,1269,1075 cm ^{-1 1} H NMR (300 MHz, CDCl ₃ ) δ 0.921 (s, 3H), 1.37-1.42 (m, 2H), 1.56 (br s, 2H), 1.77 (br s, 2H), 3.87 (s, 3H) , 4.00 (br s, 2H), 6.91 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.34 (br s, 1H), 7.68 (d, J = 16.2 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.26-8.34 (m, 4H), 8.97 (s, 1H); APCI-MS ( m/z ) 440.23(M+H) ⁺ .

Example 88

6-(2-{( E )-2-[3-methoxy-2-(pentyloxy)phenyl]vinyl}-4-oxidized- 3H -imidazo[4,5- b ]pyridine -3-yl)pyridine-3-carbonitrile

To a stirred solution of EtOAc (EtOAc) (EtOAc) After the reaction was completed, the~~~~~~~~~~ Then, the combined organic layers were washed with water (3 × 20ml), brine (20ml) and dried over ₂ SO ₄ Na, filtered and concentrated under reduced pressure. In chloroform using 1.5% methanol in diethyl ether to give the crude product was purified by silica gel column chromatography, 39mg generating ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.90 (t, J = 6.3 Hz, 3H), 1.33- 1.39 (m, 4H), 1.58 (br s, 2H), 3.89 (br s, 2H), 6.93 (d, J = 16.2 Hz, 1H), 7.07 (br s, 2H), 7.21 (br s, 1H) , 7.38 (t, J = 7.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 8.16-8.21 (m, 2H), 8.61 (d, J = 8.4 Hz, 1H), 9.12 (s, 1H); APCI-MS ( m/z ) 456.20 (M+H) ⁺ .

Example 89

6-{2-[( E )-2-(2-[cyclopropylmethoxy]-3-methoxyphenyl)ethenyl]-3 H -imidazo[4,5- b ]pyridine- 3-based nicotinonitrile

The title compound was prepared by cyclization of intermediate 42 in glacial acetic acid to afford 119 mg of pale white solid: ield (yield: s, s, s, s, s, s, s, s, s, s, s. ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.26 (d, J = 4.8 Hz, 2H), 0.53 (d, J = 7.2 Hz, 2H), 1.6 (br s, 1H), 3.87 (s, 5H), 6.90 (d, J = 4.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.30-7.36 (m, 1H), 7.71 ( d, J =16.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.23-8.29 (m, 2H), 8.32-8.40 (m, 2H), 8.97 (s, 1H); APCI-MS ( m/z ) 424.21 (M+H) ⁺ .

Example 90

6-[2-{( E )-2-[2-(cyclobutylmethoxy)-3-methoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridine-3- Nicotinonitrile

The title compound was prepared by cyclization of intermediate 43 in glacial acetic acid to give 153 mg (yield: s, s, s, s, s, s, s, s, s, s, s, s, s, ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.83 (s, 4H), 2.03 (d, J = 5.7 Hz, 2H), 2.66 (br s, 1H), 3.82 (s, 3H), 3.94 (d, J = 6.3 Hz, 2H), 7.07 (s, 1H), 7.29 (br s, 1H), 7.42-7.46 (m, 2H), 7.52 (s, 1H), 8.19 (br s, 2H) , 8.25 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 9.23 (s, 1H); ESI-MS ( m/z ) 438.18 (M +H) ⁺ .

Example 91

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridine-3- Nicotinic nitrile

As described in Example 52, the title compound was prepared by cyclization of glacial acetic acid manipulation Intermediate 39, 27mg generated off-white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 1.68-1.74 (m, 4H), 1.76-1.86 (m, 4H), 3.87 (s, 3H), 4.90 (br s, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.03 (d, J = 7.8 Hz, 1H), 7.10 ( t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.61-7.67 (m, 2H), 8.11 (s, 1H), 8.20-8.28 (m , 2H), 9.04 (s, 1H); APCI-MS ( m/z ) 438.13 (M+H) ⁺ .

Example 92

6-(2-{( E )-2-[2-(cyclopentyloxy)-3-methoxyphenyl]ethenyl}-4-oxidation- 3H -imidazo[4,5- b ] Pyridin-3-yl)pyridine-3-carbonitrile

As described in Example 88, in acetic acid using inter (3ml) m-chloroperbenzoic acid (64mg, 0.365mmol) was prepared from the title compound of Example 91 (80mg, 0.183mmol), 26mg generated off-white solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.55-1.65 (m, 4H), 1.65-1.75 (m, 4H), 3.81 (s, 3H), 4.88 (br s, 1H), 6.89 (d, J = 15.9 Hz, 1H), 7.06 (br s, 2H), 7.21 (d, J = 6.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.94 (d) , J = 7.8 Hz, 1H), 8.15 (d, J = 6.9 Hz, 1H), 8.22 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 9.12 (s, 1H); APCI-MS ( m/z ) 454.13(M+H) ⁺ .

Example 93

6- {6-Chloro -2 - [(E) -2- ( 2- pentyloxy-3-methoxyphenyl) vinyl] -3 H - imidazo [4,5- b] pyridin-3 -based nicotinonitrile

As described in Example 52, the title compound was prepared in glacial acetic acid manipulation by cyclization of Intermediate 45, 143mg generated off-white solid; IR (KBr) 2959,2253,1589,1477,1267,1081,734 cm ^{-1 1} H NMR (300 MHz, CDCl ₃ ) δ 0.926 (t, J = 6.9 Hz, 3H), 1.35-1.44 (m, 4H), 1.77 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H) ), 4.00 (t, J = 6.9 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 16.2 Hz, 1H), 8.09 (s, 1H), 8.21-8.29 (m, 2H), 8.39 (d, J = 16.2 Hz, 1H), 8.97 (s, 1H); APCI-MS ( m/z ) 474.30 (M+H) ⁺ .

Example 94

6-(6-Chloro-2-{( E )-2-[2-(cyclobutylmethoxy)-3-methoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ] Pyridin-3-yl)nicotinonitrile

As described in Example 52, in glacial acetic acid manipulation by cyclization of intermediate 46 to prepare the title compound, 58mg generating an off-white solid ^{product; IR (Neat) 3019,2238,1589,1404,1215,758 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.80-1.94 (m, 4H), 2.06-2.12 (m, 2H), 2.70-2.79 (m, 1H), 3.87 (s, 3H), 4.01 (d, J = 6.9 Hz, 2H), 6.91 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 16.2 Hz , 1H), 8.07 (s, 1H), 8.21 - 8.31 (m, 3H), 8.36 (s, 1H), 8.97 (s, 1H); ESI-MS ( m/z ) 472.21. (M+H) ⁺ .

Example 95

6-{6-Chloro-2-[( E )-2-(2-(cyclopentyloxy)-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ] Pyridin-3-yl}nicotinonitrile

As described in Example 52, the title compound was prepared by cyclization of intermediate 47 in glacial acetic acid manipulation, 52mg generated off-white solid; IR (KBr) 2962,2227,1575,1477,1266,1070,771 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.60-1.70 (m, 4H), 1.71-1.77 (m, 4H), 3.82 (s, 3H), 4.89 (br s, 1H), 7.08 (s) , 2H), 7.30 (s, 1H), 7.43 (d, J = 16.2 Hz, 1H), 8.18-8.23 (m, 1H), 8.29 (s, 1H), 8.38 (s, 2H), 8.71 (d, J = 7.8 Hz, 1H), 9.23 (s, 1H); APCI-MS ( m/z ) 472.21 (M+H) ⁺ .

Example 96

6-(2-{( E )-2-[3-(Difluoromethoxy)-2-pentyloxyphenyl]vinyl}-3 H -imidazo[4,5- b ]pyridine-3 -based nicotinonitrile

As described in Example 52, the title compound was prepared by cyclization of glacial acetic acid manipulation Intermediate 48, 71mg generated off-white ^{solid; IR (KBr) 2927,2236,1638,1413,1215,757 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.928 (t, J = 6.9 Hz, 3H), 1.33-1.47 (m, 4H), 1.74-1.81 (m, 2H), 4.02 (t, J = 6.9 Hz, 2H) ), 6.56 (t, J = 74.7 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.34 - 7.39 (m, 1H), 7.45 (d) , J = 7.5 Hz, 1H), 7.72 (d, J = 16.2 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.26-8.31 (m, 2H), 8.33 - 8.38 (m, 2H) , 8.96 (s, 1H); ESI-MS ( m/z ) 476.17 (M+H) ⁺ .

Example 97

6-(2-{( E )-2-[2-(cyclobutylmethoxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridine- 3-based nicotinonitrile

As described in Example 52, the title compound was prepared by cyclization of glacial acetic acid manipulation Intermediate 49, 86mg generated off-white solid; IR (KBr) 2941,2232,1493,1265,1124,1033,774 cm ^{-1 1} H NMR (300 MHz, CDCl ₃ ) δ 1.86 (br s, 4H), 2.10 (br s, 2H), 2.76 (t, J = 7.2 Hz, 1H), 4.02 (d, J = 6.6 Hz, 2H ), 6.56 (t, J = 74.7 Hz, 1H), 7.07-7.18 (m, 2H), 7.34-7.40 (m, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 15.9 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.27-8.36 (m, 4H), 8.97 (s, 1H); APCI-MS ( m/z ) 474.25 (M+H) ⁺ .

Example 98

6-(2-{( E )-2-[2-(cyclopentyloxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridine- 3-based nicotinonitrile

As described in Example 52, by manipulation of glacial acetic acid Intermediate 50 The title compound was prepared cyclized to produce an off-white solid product ^{93mg; IR (KBr) 2943,2230,1594,1409,1265,1048,798 cm -1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.72 (m, 4H), 1.74-1.88 (m, 4H), 4.84 (br s, 1H), 6.55 (t, J = 75.3 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.33 - 7.39 (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 16.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.27-8.36 (m, 4H), 8.97 (s, 1H); ESI-MS ( m/z ) 474.09 (M+H) ⁺ .

Example 99

2-[( E )-2-(2-cyclobutylmethoxy-3-difluoromethoxyphenyl)vinyl]-3-[4-(trifluoromethyl)phenyl]-3 H -imidazole And [4,5- b ]pyridine

As described in Example 52, the title compound was prepared by cyclization of intermediate 54 in glacial acetic acid manipulation, 47mg generated off-white ^{solid; IR (KBr) 2981,1420,1321,1102,1068,791 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.76-1.89 (m, 4H), 1.92-2.02 (m, 2H), 2.55-2.62 (m, 1H), 3.96 (d, J = 6.0 Hz, 2H), 6.53 (t, J = 72.0 Hz, 1H), 7.04-7.16 (m, 3H), 7.29-7.35 (m, 2H), 7.68 (d, J = 6.0 Hz, 2H), 7.92 (d, J = 6.0 Hz, 2H), 8.12 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 15.0 Hz, 1H), 8.35 (br s, 1H); ESI-MS ( m/z ) 516.22 (M+H) ⁺ .

Example 100

2-{( E )-2-[2-cyclobutylmethoxy-3-(difluoromethoxy)phenyl]vinyl}-3-[4-(trifluoromethoxy)phenyl]-3 H -imidazo[4,5- b ]pyridine

The title compound was prepared by cyclization of Intermediate 55 in EtOAc (EtOAc) EtOAc (EtOAc: EtOAc ^{: 1} ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.77-1.90 (m, 4H), 1.93-2.01 (m, 2H), 2.59 (t, J = 6.0 Hz, 1H), 3.96 (d, J = 6.0) Hz, 2H), 6.53 (t, J = 72.0 Hz, 1H), 7.06-7.11 (m, 3H), 7.26-7.32 (m, 3H), 7.53 (dd, J = 6.0, 15.0 Hz, 3H), 8.11 (d, J = 6.0 Hz, 1H), 8.18 (d, J = 15.0 Hz, 1H), 8.35 (br s, 1H); ESI-MS ( m/z ) 532.23 (M+H) ⁺ .

Example 101

6-(6-Chloro-2-{( E )-2-[3-(difluoromethoxy)-2-pentyloxyphenyl]vinyl}-3 H -imidazo[4,5- b Pyridin-3-yl)nicotinonitrile

As described in Example 52, the title compound was prepared by cyclization of intermediate 51 in glacial acetic acid manipulation, generating an off-white solid product ^{30mg; IR (KBr) 2930,2234,1413,1273,1135,701 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 0.93 (s, 3H), 1.38-1.44 (m, 4H), 1.79 (br s, 2H), 4.02 (s, 2H), 6.56 (t, J = 74.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.43 (br s, 1H), 7.69 (d, J = 16.2 Hz, 1H), 8.04 (s, 1H), 8.28 (s, 4H), 8.96 (s, 1H); ESI-MS ( m/z ) 510.17 (M+H) ⁺ .

Example 102

6-(6-Chloro-2-{( E )-2-[2-(cyclobutylmethoxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile

As described in Example 52, the title compound was prepared in glacial acetic acid manipulation by cyclization of Intermediate 52, 49mg generated off-white ^{solid; IR (KBr) 2926,2236,1497,1215,1120,758 cm -1} ; 1 H NMR (300 MHz, CDCl ₃ ) δ 1.85 (br s, 4H), 2.05 (br s, 2H), 2.63 (br s, 1H), 3.96 (br s, 2H), 7.18-7.28 (m, 4H) , 7.53 (d, J = 15.6 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 8.17-8.3 (m, 2H), 8.40 (s, 1H), 8.72 (d, J = 6.9 Hz, 1H), 9.23 (s, 1H); ESI-MS ( m/z ) 508.19 (M+H) ⁺ .

Example 103

6-(6-Chloro-2-{( E )-2-[2-(cyclopentyloxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile

As described in Example 52, the title compound was prepared by cyclization of glacial acetic acid manipulation Intermediate 53, 48mg generated off-white solid; IR (KBr) 2950,2231,1588,1401,1267,1044,770 cm ^{-1 1} H NMR (300 MHz, CDCl ₃ ) δ 1.57-1.65 (m, 4H), 1.72-1.88 (m, 4H), 4.84 (br s, 1H), 6.54 (t, J = 74.7 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.45 (br s, 1H), 7.64 (d, J = 16.2 Hz, 1H), 8.09 (s, 1H) , 8.27-8.35 (m, 4H), 8.97 (s, 1H); ESI-MS ( m/z ) 508.10 (M+H) ⁺ .

Example 104

6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)ethenyl]-1 H -imidazo[4,5- c ]pyridine-1- Nicotinic nitrile

As described in Example 52, the title compound was prepared in glacial acetic acid manipulation by cyclization of Intermediate 44, 19mg generated off-white ^{solid; IR (KBr) 2957,2232,1590,1480,1266,1048 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 1.56-1.66 (m, 4H), 1.73-1.77 (m, 4H), 3.82 (s, 3H), 4.89 (s, 1H), 7.08 (s, 2H) , 7.30 (d, J = 16.2 Hz, 2H), 7.61 (br s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 16.2 Hz, 1H), 8.43 (br s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 9.10 (s, 1H), 9.27 (s, 1H); APCI-MS ( m/z ) 438.24 (M+H) ⁺ .

Pharmacological activity

According to T The improved process described by th, A., Kedei, N., Wang, Y. and Blumberg, PM, Life Sciences, (2003), 73 , 487-498 screens for TRPV3 activity of exemplary embodiments of the invention. Screening of compounds can be carried out by other methods and procedures known to those skilled in the art. These screening methods can be found in (a) Hu, H.-Z. et al . J. Biol. Chem . (2004), 279 , 35741-35747; (b) Smith, GD et al, Nature (2002), 418 , 186-190; (c) Peier, AM et al, Science (2002), 296 , 2046-2049.

Screening for TRPV3 antagonists using ⁴⁵ calcium absorption assays:

Inhibition of TRPV3 receptor activation was examined by inhibition of cellular uptake induced by radioactive calcium 2-aminoethoxydiphenylborate (2-APB). The test compound was dissolved in dimethyl hydrazine (DMSO) to prepare a 20 mM stock solution, which was then diluted with DMEM/F-12 plain medium containing 1.8 mM CaCl ₂ to obtain the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPV3 expressing CHO cells was grown in DMEM/F-12 medium containing 10% FBS, 1% penicillin-streptomycin solution and 400 μg/ml G-418. At 24 h prior to analysis, cells were seeded in 96-well plates such that ~50,000 cells/well were obtained on the day of the experiment. The cells were treated with the test compound for 10 minutes and then added to a final concentration of 500 μM of 2-APB and 5 μCi/ml of ⁴⁵ Ca ⁺² over 4 minutes. The cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. The radioactivity in the lysate was measured in a Packardt Top count after the addition of a liquid scintillant. The concentration response curve was plotted as the maximum response % obtained in the absence of the test antagonist. Using the GraphPad PRISM software, IC ₅₀ values can be calculated from the concentration response curve by nonlinear regression analysis.

Each of the prepared compounds was tested using the above analysis procedure, and the results obtained are shown in Table 4. For the selected examples, % inhibition at 1.0 μM and 10.0 μM along with IC ₅₀ (nM) details are shown in the table. The IC ₅₀ (nM) values for these compounds are illustrated in Table 4, where "A" means an IC ₅₀ value of less than 50 nM, "B" means an IC ₅₀ value of 50.01 - 100.0 nM, and "C" means IC _{The 50} value is in the range of 100.01-500.0 nM, and "D" means that the IC ₅₀ value is higher than 500.0 nM.

Although the present invention has been described herein with reference to the specific embodiments thereof, it is understood that these embodiments are merely illustrative of the principles and applications of the invention. Therefore, it is to be understood that many modifications may be made to the illustrative embodiments, and it is understood that other aspects can be devised without departing from the spirit and scope of the invention as described.

All publications, patents, and patent applications cited in this application are hereby incorporated by reference in their entirety in their entirety in the the the the the the the

Claims (10)

a compound of formula (I), Or a pharmaceutically acceptable salt thereof, wherein X is independently selected from C or N; when X is N, it is optionally oxidized to form an oxide of N; and R ^{1 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro , cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, -S(O) _p R ⁵ (where p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm' is an integer from 1 to 4, inclusive; Q is hydrogen, substituted or not Substituted alkyl, haloalkyl, aryl, arylalkyl, heteroaryl; wherein the substituent may be one or more, and independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl and cycloalkoxy; R ² and R ³ may be the same or different, independently Selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl , heteroaryl, heteroarylalkyl, hetero a cyclic group and a heterocyclylalkyl group; R ^{4 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, amine, -COOR ^a , substituted or unsubstituted alkyl, alkenyl, alkoxy, Haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl; R ^{a is} independently selected from hydrogen or substituted or unsubstituted alkyl; R ⁵ and R ⁶ may be the same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, cycloalkylalkyl, arylalkyl and hetero An arylalkyl group; and 'n' is an integer from 0 to 3, inclusive, wherein X is preferably a substituted or unsubstituted phenyl, benzyl or pyridine. The compound of claim 1, wherein the compound has the formula (II): Or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -S(O) _p R ⁵ (where p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm ' is an integer from 1 to 4, inclusive; Q is hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, arylalkyl, heteroaryl; wherein the substituent may be One or more, and independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, Haloalkoxy, cycloalkyl and cycloalkoxy; R ^a is hydrogen or substituted or unsubstituted alkyl; R ² and R ³ may be the same or different and are independently selected from the group consisting of hydrogen: , substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero a cyclic group and a heterocyclic alkyl group; And R ⁵ and R ⁶ may be the same or different, are independently selected from hydrogen, a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, cycloalkylalkyl, arylalkyl and Heteroarylalkyl. The compound of claim 1, wherein the compound has the formula (III): Or a pharmaceutically acceptable salt thereof, wherein X is C or N; when X is N, it is optionally oxidized to form an oxide of N; Z is independently selected from C or N; and R ^{1 is} independently selected from hydrogen, Halogen, hydroxy, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, hetero Aryl, heteroarylalkyl, -S(O) _p R ⁵ (wherein p is 1 or 2) and -SO ₂ NR ⁵ R ⁶ ; 'm' is an integer from 1 to 4, inclusive; ⁷ may be the same or different and are independently selected from the group consisting of halogen, hydroxy, nitro, cyano, amine, COOR ^a , C(O)NR ⁵ R ⁶ , substituted or unsubstituted alkyl, alkoxy, haloalkyl, Haloalkoxy, cycloalkyl and cycloalkoxy; R ^a is hydrogen or substituted or unsubstituted alkyl; R ² and R ³ may be the same or different and are independently selected from the group consisting of hydrogen: , substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroaryl Alkyl and heterocyclylalkyl; R ⁵ and R ⁶ may be the same Or different, independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; r' is an integer from 1 to 5, inclusive. The compound of claim 1, wherein the compound is selected from the group consisting of: 2-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl}- 1-pyridin-2-yl-1 H -benzimidazole; 2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-pyridine-2- yl -1 H - benzo imidazole; 1- (5-chloro-pyridin-2-yl) -2 - {(E) -2- [2- ( cyclopentyloxy) -3-methoxyphenyl] vinyl }}-1 H -benzimidazole; 2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1-(5-nitropyridine- 2-yl)-1 H -benzimidazole; 2-[( E )-2-(2-benzyloxy-3-methoxyphenyl)vinyl]-1-(3,5-dichloropyridine -2-yl)-1 H -benzimidazole; 1-(3,5-dichloropyridin-2-yl)-2-{( E )-2-[2-(2-fluorobenzyloxy)- 3-methoxyphenyl]vinyl}-1 H -benzimidazole; 2-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl] -1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-butoxy-3-methoxyphenyl)vinyl]-1 H -benzene And imidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-isopropoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole-1 -yl}nicotinonitrile; 6-{2-[( E )-2-(2-(1-ethylpropoxy)-3-methoxyphenyl )vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-(2-{( E )-2-[3-methoxy-2-(2-methylpropoxy)benzene Vinyl}-1 H -benzimidazol-1-yl)pyridine-3-carbonitrile; 6-{2-[( E )-2-(2-[cyclopropylmethoxy]-3-methyl Oxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl) )vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-(2-{( E )-2-[2-(2-fluorobenzyloxy)-3-methoxyphenyl ]vinyl}-1 H -benzimidazol-1-yl)nicotinonitrile; 6-{2-[( E )-2-(2-(2-cyanobenzyloxy-3-methoxyphenyl) )vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(3-methoxy-2-{[2-(trifluoromethyl)) Benzyl]oxy}phenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-(2-{( E )-2-[2-(2,6-difluorobenzyl) Oxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl)nicotinonitrile; 6-(2-{( E )-2-[2-(2,4- Difluorobenzyloxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazol-1-yl)nicotinonitrile; 6-{2-[( E )-2-(2-[ring Ethyl pentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzoimidazol-1-yl}pyridazine-3-carboxylate; 6-{2-[( E )-2- (2-[cyclopentyloxy]-3-methoxy Phenyl) vinyl] -1 H - benzimidazol-1-yl} pyridazine-3-carbonitrile; 2 - {(E) -2- [2- cyclopentyloxy) -3-methoxyphenyl ]vinyl}-1-pyrimidin-2-yl-1 H -benzimidazole; 1-(5-bromopyrimidin-2-yl)-2-{( E )-2-[2-(1-ethyl Propoxy)-3-methoxyphenyl]ethenyl}-1 H -benzimidazole; 1-(5-bromopyrimidin-2-yl)-2-[( E )-2-(2-ring Pentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole; 2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl 1-[3-(trifluoromethyl)pyridin-2-yl]-1 H -benzimidazole; 2-[( E )-2-(2-isopropoxy-3-methoxybenzene) Vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzimidazole; 2-[( E )-2-(2-cyclopropoxy-3-methoxy Phenyl)vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzimidazole; 2-[( E )-2-(2-cyclopentyloxy-3- Methoxyphenyl)vinyl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1 H -benzimidazole; 2-[( E )-2-(2-benzyloxy 3-methoxyphenyl)vinyl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1 H -benzimidazole; 1-[3-chloro-5-(trifluoro methyl) pyridin-2-yl] -2 - [(E) -2- (2- cyclopentyloxy-3-methoxyphenyl) vinyl] -1 H - benzo Oxazole; 6- (2 - {(E ) -2- [2- ( cyclopentyloxy) -3-methoxyphenyl] ethenyl} -1 H - benzimidazol-1-yl) nicotinic acid A Ester; 2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1-(4-methylphenyl)-1 H -benzimidazole ;2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-(2-methoxyphenyl)-1 H -benzimidazole; 4 -{2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzoimidazol-1-yl}benzonitrile; 4-{ 2-[( E )-2-(2-benzyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}benzonitrile; 2-[( E )-2 -(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-[4-(trifluoromethyl)phenyl]-1 H -benzimidazole; 4-{2-[( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}benzonitrile; 2-[( E )-2-(2- Cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1-[4-(trifluoromethyl)phenyl]-1 H -benzimidazole; 5-{2-[( E ) -2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-4-fluorobenzonitrile; 4-{2-[( E) -2- (2- cyclopropylmethoxy-3-methoxyphenyl) vinyl] -1 H - benzimidazol-1-yl} -3-fluoro-benzonitrile 2 - [(E) -2- ( 2- cyclopentyloxy-3-methoxyphenyl) vinyl] -1- (4-tert-butylbenzyl) -1 H - benzo imidazole; 1- (2,4-difluorobenzyl)-2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazole; 4 -({2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}methyl)benzonitrile 4-({2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}methyl)benzonitrile 4-({2-[( E )-2-(2-{2-fluorobenzyloxy}-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}A Benzyl nitrile; 2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)]-1-(2-thienyl)-1 H -benzimidazole; 2-[( E )-2-(2-cyclopropoxy-3-methoxyphenyl)vinyl]-1-(1,3-thiazol-2-yl)-1 H -benzimidazole; 2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1-(1,3-thiazol-2-yl)-1 H -benzimidazole; 2-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}-1,3- Thiazol-5-carbonitrile; 2-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}- 4-methyl-1,3- Oxadiazol-5-carbonitrile; 2- {2 - [(E ) -2- (2- cyclopropylmethoxy-3-methoxyphenyl) vinyl] -1 H - benzimidazol-1-yl }-1,3-benzothiazole; 6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-methoxy-1 H -benzimidazol-1-yl}nicotinonitrile; 6-(6-chloro-2-{( E )-2-[3-methoxy-2-(2-methylpropoxy)phenyl]ethene }}-1 H -benzimidazol-1-yl)pyridin-3-carbonitrile; 6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)ethene 6-fluoro-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{6-chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxy Phenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{5-chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxy Phenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl )vinyl]-5-methoxy-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methyl Oxyphenyl)vinyl]-5-(trifluoromethyl)-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{6-(difluoromethoxy)-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )- 2-(2-[cyclopentyloxy]-3-methyl Phenyl) vinyl] -5- (difluoromethoxy) -1 H - benzimidazol-1-yl} nicotinonitrile; 6- {2 - [(E ) -2- (2- oxo-cyclopentyl Methyl 3-methoxyphenyl)vinyl]-6-fluoro-1 H -benzimidazol-1-yl}methyl nicotinate; 2-{2-[( E )-2-(2-ring) Pentyloxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-( 2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-5,6-dimethyl-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-ethoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2- [( E )-2-(2-Butoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}-nicotinonitrile; 6- {5,6-Difluoro-2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{5,6-Difluoro-2-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nicotinonitrile; 6-{2-[( E )-2-(2-cyclobutylmethoxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazole-1 -based nicotinonitrile; 6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazole -1-base} smoke Nitrile; 6-{5,6-difluoro-2-[( E )-2-(2-hydroxy-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nitrile; 6-{6-chloro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-5-fluoro-1 H -benzimidazole -1-yl}nicotinonitrile; 6-{5-chloro-2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-6-(trifluoromethyl) yl) -1 H - benzimidazol-1-yl} nicotinonitrile; 6- {5,6-dichloro -2 - [(E) -2- ( 2- cyclopentyloxy-3-methoxybenzoate Vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6-{2-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl ]-5,6-difluoro-1 H -benzimidazol-1-yl}pyridazine-3-carboxylic acid ethyl ester; 6-{2-[( E )-2-(2-cyclopentyloxy- 3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}pyridazine-3-carboxylic acid; 6-{2-[( E )-2- (2-cyclopentyloxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}pyridazine-3-decylamine; 6-{2 -[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H -benzimidazol-1-yl}pyridazine-3 - nitrile; 6-{2-[( E )-2-(2-(1-ethylpropoxy)-3-methoxyphenyl)vinyl]-5,6-difluoro-1 H - Benzimidazol-1-yl}nicotinonitrile; 6-{5,7-di -2 - [(E) -2- ( 2- pentyloxy-3-methoxyphenyl) vinyl] -1 H - benzimidazol-1-yl} nicotinonitrile; 6- {5,7 Difluoro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl}nicotinonitrile; 6- {4,6-Difluoro-2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-1 H -benzimidazol-1-yl} Nicotinonitrile; 6-{2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-4,5,6-trifluoro-1 H -benzimidazole- 1-yl}nicotinonitrile; 6-(2-{( E )-2-[3-(difluoromethoxy)-2-pentyloxyphenyl]vinyl}-5,6-difluoro-1 H -benzimidazol-1-yl)nicotinonitrile; 6-(2-{( E )-2-[2-(cyclobutylmethoxy)-3-difluoromethoxyphenyl]vinyl}-5 ,6-difluoro-1 H -benzimidazol-1-yl)nicotinonitrile; 6-(2-{( E )-2-[2-(cyclopentyloxy)-3-difluoromethoxybenzene Vinyl}-5,6-difluoro-1 H -benzimidazol-1-yl)nicotinonitrile; 2-[( E )-2-(2-butoxy-3-methoxyphenyl) )vinyl]-1-(5-trifluoromethylpyridin-2-yl)-1 H -benzimidazole; 6-{2-[( E )-2-(2-butoxy-3-methyl) Oxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl}nicotinonitrile; 6-{2-[( E )-2-(2-pentyloxy-3) -methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl}nicotinonitrile; 6-(2-{( E )-2-[3-methoxy-2-(pentyloxy)phenyl]vinyl }-4-Oxo-3 H -imidazo[4,5- b ]pyridin-3-yl)pyridine-3-carbonitrile; 6-{2-[( E )-2-(2-[cyclopropyl A Oxy]-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl}nicotinonitrile; 6-[2-{( E )-2-[ 2-(cyclobutylmethoxy)-3-methoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridin-3-yl]nicotinonitrile; 6-{2-[( E )-2-(2-[cyclopentyloxy]-3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl}nicotinonitrile; 6-( 2-{( E )-2-[2-(cyclopentyloxy)-3-methoxyphenyl]ethenyl}-4-oxo- 3H -imidazo[4,5- b ]pyridine-3 -yl)pyridine-3-carbonitrile; 6-{6-chloro-2-[( E )-2-(2-pentyloxy-3-methoxyphenyl)vinyl]-3 H -imidazo[ 4,5- b ]pyridin-3-yl}nicotinonitrile; 6-(6-chloro-2-{( E )-2-[2-(cyclobutylmethoxy)-3-methoxyphenyl]ethene }}-3 H -imidazo[4,5-b]pyridin-3-yl)nicotinonitrile; 6-{6-chloro-2-[( E )-2-(2-(cyclopentyloxy)- 3-methoxyphenyl)vinyl]-3 H -imidazo[4,5- b ]pyridin-3-yl}nicotinonitrile; 6-(2-{( E )-2-[3-(two Fluoromethoxy)-2-pentyloxyphenyl] Alkenyl yl} -3 H - imidazo [4,5- b] pyridin-3-yl) nicotinonitrile; 6- (2 - {(E ) -2- [2- ( cyclobutyl methoxy) -3- Fluoromethoxyphenyl]vinyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile; 6-(2-{( E )-2-[2-(cyclopentyl) Oxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile; 2-[( E )-2-(2 - cyclobutyl methoxy-3-difluoromethoxy-phenyl) vinyl] -3- [4- (trifluoromethyl) phenyl] -3 H - imidazo [4,5- b] pyridine; 2 -{( E )-2-[2-cyclobutylmethoxy-3-(difluoromethoxy)phenyl]vinyl}-3-[4-(trifluoromethoxy)phenyl]-3 H Imidazo[4,5- b ]pyridine; 6-(6-chloro-2-{( E )-2-[3-(difluoromethoxy)-2-pentyloxyphenyl]vinyl}- 3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile; 6-(6-chloro-2-{( E )-2-[2-(cyclobutylmethoxy)-3-di Fluoromethoxyphenyl]vinyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile; 6-(6-chloro-2-{( E )-2-[2 -(cyclopentyloxy)-3-difluoromethoxyphenyl]ethenyl}-3 H -imidazo[4,5- b ]pyridin-3-yl)nicotinonitrile; and 6-{2-[ (E) -2- (2- [cyclopentyloxy] -3-methoxyphenyl) vinyl] -1 H - imidazo [4,5- c] pyridin-1-yl} Nitrile; or pharmaceutically acceptable salts of the above compounds. A compound according to any one of claims 1 to 4 for the preparation of a medicament for preventing, ameliorating or treating a syndrome, disease or disorder mediated by a vanilloid receptor in a subject in need thereof Use. The use of the fifth aspect of the patent application, wherein the symptoms of the disease, disorder, syndrome or condition associated with TRPV3 function are selected from the group consisting of: pain; acute pain; chronic pain; nociceptive pain; Sexual pain; postoperative pain; toothache; cancer pain; heartache caused by ischemic myocardium; pain caused by migraine; joint pain; neuropathy; neuralgia; trigeminal neuralgia; nerve injury; diabetic neuropathy; neurodegenerative disease Retinopathy; neuropathic skin disorder; stroke; bladder allergy; urinary incontinence; vulvar pain; gastrointestinal disorders, such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory Enteropathy, Crohn's disease, celiac disease; inflammatory diseases such as pancreatitis; respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; skin, eye or mucous membrane irritation; dermatitis; itching Symptoms, such as uremia, itching; fever; muscle spasm; vomiting; dyskinesia; depression; Huntington's disease; memory loss; brain function Limit; amyotrophic lateral sclerosis (ALS); dementia; arthritis; osteoarthritis; diabetes; obesity; urticaria; actinic keratosis; keratoacanthoma; alopecia; Tinnitus; hypersensitivity; anxiety; and benign prostatic hyperplasia. A use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of pain in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a medicament Preferably, the pain is acute pain, chronic pain or postoperative pain. The use of claim 6, wherein the use is in the manufacture of a medicament for the treatment of osteoarthritis or rheumatoid arthritis. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of neuropathic pain or inflammation in a patient in need thereof, which comprises administering to the subject a therapeutically effective amount Drug. The patentable scope of application of the compound of item 1, wherein the compound or a pharmaceutically acceptable salt thereof having IC ₅₀ of less than 100 nM, and the IC ₅₀ Determination of calcium absorbed through ^45.